Biology and Therapeutic Potential of the Interleukin-4/interleukin-13 Signaling Pathway in Asthma

American Journal of Respiratory Medicine : Drugs, Devices, and Other Interventions. 2002  |  Pubmed ID: 14720056

The future management of patients with allergic asthma is poised to change in the coming one to two decades. This prediction is based on fundamental new insights into the pathogenesis of disease, gained through the study of both humans and experimental models of asthma. These studies have revealed that allergic asthma is an immune-mediated disease which, despite the redundancy characteristic of all immune responses, may be induced through a single dominant signaling cascade called the interleukin (IL)-4/IL-13 signaling pathway. In addition to the cytokine IL-4, this pathway includes IL-13, the cytokine receptor subunit IL-4 receptor alpha (IL-4Ralpha), Janus-associated tyrosine kinases and the transcription factor, signal transducer and activator of transcription 6. The IL-4 signaling pathway controls the most important cellular developmental (afferent) events that underlie asthma. These include T helper (Th) type 2 cell activation, B cell activation and immunoglobulin (Ig) E secretion, mast cell development, and effector (efferent) events related exclusively to immune effects on the lung such as goblet cell metaplasia and airway hyperresponsiveness. Any of the IL-4 signaling molecules are potentially amenable to pharmacological intervention, but a detailed understanding of the entire pathway is required to appreciate their actual potential for drug development. For example, neutralization strategies that target only IL-4 are unlikely to succeed because they leave IL-13 free to continue the signaling cascade. In contrast, neutralization of IL-4Ralpha may represent a more feasible strategy, as it should prevent signaling by both IL-4 and IL-13. The therapeutic potential of targeting intracytoplasmic tyrosine kinases has already been achieved with the use of small molecules, suggesting that this approach may be realistically adopted for the treatment of asthma. However, well designed asthma clinical trials are warranted to determine with certainty, the efficacy of therapies based on IL-4/IL-13 blockade.

Shedding Light on Sheddases: Role in Growth and Development

BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology. Jan, 2002  |  Pubmed ID: 11782944

The extracellular domains of several integral membrane proteins are released from the cell surface by a group of enzymes known as "sheddases" through a process called "ectodomain shedding". Because many transmembrane growth and differentiation factors, including members of the epidermal growth factor (EGF) family that play a crucial role in development, require ectodomain shedding for proper action in vivo, proteolysis is now viewed as a regulatory mechanism in the developing embryos. Two recent reports by Zhao et al. provide evidence for the role of cell surface proteolysis by an ADAM (a disintegrin and metalloprotease) in the development of murine lung. Inhibition of tumor necrosis factor-alpha converting enzyme (TACE, ADAM17) by the hydroxamic acid-based metalloprotease inhibitor (TAPI), or a targeted mutation in Zn(2+)-binding domain of TACE, disrupts two essential epithelial functions in lung development: branching morphogenesis and cytodifferentiation. Evidence for the role of ADAMs as sheddases in development and growth factor signaling is discussed.

Signaling Through the EGF Receptor Controls Lung Morphogenesis in Part by Regulating MT1-MMP-mediated Activation of Gelatinase A/MMP2

Journal of Cell Science. Feb, 2002  |  Pubmed ID: 11865039

Epithelial-mesenchymal interactions during lung development require extracellular signaling factors that facilitate branching morphogenesis. We show here that matrix metalloproteinases (MMPs) originating in the mesenchyme are necessary for epithelial branching and alveolization. We found that the delayed lung maturation characterized by abnormal branching and poor alveolization seen in mice deficient in epidermal growth factor receptor (Egfr(-/-)) is accompanied by aberrant expression of MMPs. By in situ zymography, the lungs from newborn Egfr(-/-) mice had low gelatinolytic activity compared with wildtype. Inhibition of MMPs in developing lungs in vivo or in vitro severely retarded morphogenesis. Egfr(-/-) mice had low expression of MT1-MMP/MMP14, which is a potent activator of gelatinase A/MMP2, in their lungs. Egf ligand increased MT1-MMP mRNA by tenfold in lung fibroblasts from wild type, but not from Egfr(-/-) mice. Extracts from lungs of Egfr(-/-) mice showed a tenfold reduction in active MMP-2, but only a slight decrease in proMMP-2 by zymography. At birth, MMP-2(-/-) mice had a lung phenotype characterized by abnormal lung alveolization which phenocopied that of Egfr(-/-) mice, albeit somewhat less severe. We conclude that proteolysis mediates epithelial/mesenchymal interactions during lung morphogenesis. From the phenotypes of the Egfr(-/-) mice, we identify MT1-MMP as a major downstream target of Egfr signaling in lung in vivo and in vitro. MT1-MMP is, in turn, necessary for activation of MMP-2, a mesenchymal enzyme that is required for normal lung morphogenesis.

Decreased Allergic Lung Inflammatory Cell Egression and Increased Susceptibility to Asphyxiation in MMP2-deficiency

Nature Immunology. Apr, 2002  |  Pubmed ID: 11887181

Clearance of recruited immune cells is necessary to resolve inflammatory reactions. We show here that matrix metalloproteinase 2 (MMP2), as part of an interleukin 13 (IL-13)-dependent regulatory loop, dampens inflammation by promoting the egress of inflammatory cells into the airway lumen. MMP2-/- mice showed a robust asthma phenotype and increased susceptibility to asphyxiation induced by allergens. However, whereas the lack of MMP2 reduced the influx of cells into bronchoalveolar lavage (BAL), numerous inflammatory cells accumulated in the lung parenchyma. BAL of MMP2-/- mice lacked normal chemotactic activity, whereas lung inflammatory cells from the same mice showed appropriate chemotactic responses. Thus, MMP2 establishes the chemotactic gradient required for egression of lung inflammatory cells and prevention of lethal asphyxiation.

Gene Therapy of Mucus Hypersecretion in Experimental Asthma

Chest. Mar, 2002  |  Pubmed ID: 11893719

Environmental Contributions to the Allergic Asthma Epidemic

Environmental Health Perspectives. Aug, 2002  |  Pubmed ID: 12194885

Current data overwhelmingly document the existence of a worldwide asthma epidemic, although individual studies remain controversial. The epidemic is thought to involve primarily persons with allergic asthma, and many diverse theories, based on an immunopathologic understanding of disease, have recently emerged to explain this involvement. In the context of recent insights into the immune basis of experimental asthma, we discuss in this review the leading asthma epidemic theories, including a new theory based on inhaled environmental proteases. Although no single theory may yet be fully embraced, there exists substantial hope that a unifying mechanism for the epidemic will be revealed through additional research.

A Protease-activated Pathway Underlying Th Cell Type 2 Activation and Allergic Lung Disease

Journal of Immunology (Baltimore, Md. : 1950). Nov, 2002  |  Pubmed ID: 12421974

The respiratory allergens that induce experimental Th cell type 2-dependent allergic lung inflammation may be grouped into two functional classes. One class of allergens, in this study termed type I, requires priming with adjuvants remote from the lung to overcome airway tolerogenic mechanisms that ordinarily preclude allergic responses to inhaled Ags. In contrast, the other, or type II, allergen class requires neither remote priming nor additional adjuvants to overcome airway tolerance and elicit robust allergic lung disease. In this study, we show in an experimental model that diverse type II allergens share in common proteolytic activity that is both necessary and sufficient for overcoming airway tolerance and induction of pulmonary allergic disease. Inactivated protease and protease-free Ag fragments showed no allergenic potency, demonstrating that only active protease acting on endogenous substrates was essential. Furthermore, induction of airway tolerance could be aborted and allergic lung disease established by simply adding purified protease to a type I allergen. Thus, exogenous proteases are common to type II allergens and may be generally required to overcome the innate resistance of the airway to Th cell type 2 activation and allergic inflammation, raising concern for their potential contribution to diseases such as asthma.

16. Immunologic Lung Disease

The Journal of Allergy and Clinical Immunology. Feb, 2003  |  Pubmed ID: 12592307

This review summarizes the recent advances regarding pathogenesis, diagnosis, and treatment of immunological diseases of the lung. Rather than attempt a comprehensive analysis, we have focused on selected diseases that are of particular relevance to the practicing physician, and the material has been organized according to the dominant immunologic mechanisms underlying the disease. Because of the redundancy that characterizes the mammalian immune repertoire, this system of classification inevitably produces overlap but facilitates acquisition of what is otherwise a disparate collection of facts. The principal lung immunologic mechanisms are most broadly classified as innate or adaptive immune processes. Innate immunity includes neutrophils and complement that are important in diseases, such as pneumonia and the acute respiratory distress syndrome. Adaptive immunity involves T and B cells capable of recognizing discrete antigens. T(H)1- and T(H)2-dependent adaptive immune responses underlie some of the most common and important of lung diseases, including tuberculosis and asthma, respectively. Other important immunopathologic processes include granulomatous inflammation that characterizes sarcoidosis and Churg-Strauss vasculitis, and autoimmunity, which is characteristic of antiglomerular basement membrane disease and others.

Differential Requirement for CD18 in T-helper Effector Homing

Nature Medicine. Oct, 2003  |  Pubmed ID: 14502280

To understand the integrin requirements of T-helper (T(H)) effector subsets, we investigated the contribution of CD18 (beta(2) integrin) to T(H)1 and T(H)2 function in vitro and in relevant disease models. CD18-deficient (Itgb2(-/-)) T cells showed largely normal in vitro function. Compared with wild-type mice, Itgb2(-/-) mice were better able to resolve Leishmania major infection and generated a superior T(H)1 immune response, as assessed from draining lymph nodes. In contrast, T(H)2-dependent allergic lung disease was markedly impaired in mutant mice. In both models, development of T(H)1 and T(H)2 cells in spleens was normal, but accumulation of T(H)2 (not T(H)1) cells at inflammatory sites was reduced. Thus, CD18 is selectively required for T(H)2, but not T(H)1, homing and has a minimal influence on T-effector development. These findings suggest a new integrin-based therapeutic approach in which the outcomes of diverse diseases may be favorably influenced by altering the homing of T(H)2 cells.

Airway Glycoprotein Secretion Parallels Production and Predicts Airway Obstruction in Pulmonary Allergy

The Journal of Allergy and Clinical Immunology. Jan, 2004  |  Pubmed ID: 14713910

Airway obstruction, perhaps the most relevant clinical feature of asthma, is typically assessed in allergic asthma models as airway hyperresponsiveness. Excess secretion of airway glycoproteins also contributes to airway obstruction in asthma but is not measured as part of most experimental models.

Overlapping and Independent Contributions of MMP2 and MMP9 to Lung Allergic Inflammatory Cell Egression Through Decreased CC Chemokines

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Jun, 2004  |  Pubmed ID: 15059974

The mechanisms that initiate allergic lung inflammation are relevant to expression of diseases such as asthma, but the factors underlying resolution of inflammation are equally important. Previously, we demonstrated the importance of matrix metalloproteinase 2 (MMP2) for airway egression of lung eosinophils, a critical anti-inflammatory mechanism without which mice are rendered highly susceptible to lethal asphyxiation. Here we show that leukocyte MMP9 is the dominant airway MMP controlling inflammatory cell egression. The allergic lung phenotype of MMP9-/- mice was similar to WT and was not altered by concomitant deletion of the MMP2 gene (double knockout; dko). However, inflammatory cells accumulated aberrantly in the lungs of allergen-challenged MMP9-/- and dko mice and fewer eosinophils and neutrophils were present in bronchoalveolar lavage. These aberrant cellular trafficking patterns were explained by disruption of transepithelial chemokine gradients, in MMP2-/- mice affecting only eotaxin (CCL11), but in MMP9-/- and dko mice involving eotaxin, MARC (CCL7), and TARC (CCL17). Thus, by establishing multiple transepithelial chemokine gradients, MMP9 is broadly implicated in the resolution of allergic inflammation, an essential protective mechanism that overlaps with a more limited role played by MMP2.

Epidermal Detachment, Desmosomal Dissociation, and Destabilization of Corneodesmosin in Spink5-/- Mice

Genes & Development. Oct, 2004  |  Pubmed ID: 15466487

Netherton syndrome (NS) is a human autosomal recessive skin disease caused by mutations in the SPINK5 gene, which encodes the putative proteinase inhibitor LEKTI. We have generated a transgenic mouse line with an insertional mutation that inactivated the mouse SPINK5 ortholog. Mutant mice exhibit fragile stratum corneum and perinatal death due to dehydration. Our analysis suggests that the phenotype is a consequence of desmosomal fragility associated with premature proteolysis of corneodesmosin, an extracellular desmosomal component. Our mouse mutant provides a model system for molecular studies of desmosomal stability and keratinocyte adhesion, and for designing therapeutic strategies to treat NS.

An Immune Basis for Lung Parenchymal Destruction in Chronic Obstructive Pulmonary Disease and Emphysema

PLoS Medicine. Oct, 2004  |  Pubmed ID: 15526056

Chronic obstructive pulmonary disease and emphysema are a frequent result of long-term smoking, but the exact mechanisms, specifically which types of cells are associated with the lung destruction, are unclear.

Endogenous Attenuation of Allergic Lung Inflammation by Syndecan-1

Journal of Immunology (Baltimore, Md. : 1950). May, 2005  |  Pubmed ID: 15843578

The airway plays a vital role in allergic lung diseases by responding to inhaled allergens and initiating allergic inflammation. Various proinflammatory functions of the airway epithelium have been identified, but, equally important, anti-inflammatory mechanisms must also exist. We show in this study that syndecan-1, the major heparan sulfate proteoglycan of epithelial cells, attenuates allergic lung inflammation. Our results show that syndecan-1-null mice instilled with allergens exhibit exaggerated airway hyperresponsiveness, glycoprotein hypersecretion, eosinophilia, and lung IL-4 responses. However, administration of purified syndecan-1 ectodomains, but not ectodomain core proteins devoid of heparan sulfate, significantly inhibits these inflammatory responses. Furthermore, syndecan-1 ectodomains are shed into the airway when wild-type mice are intranasally instilled with several biochemically distinct inducers of allergic lung inflammation. Our results also show that syndecan-1 ectodomains bind to the CC chemokines (CCL7, CCL11, and CCL17) implicated in allergic diseases, inhibit CC chemokine-mediated T cell migration, and suppress allergen-induced accumulation of Th2 cells in the lung through their heparan sulfate chains. Together, these findings uncover an endogenous anti-inflammatory mechanism of the airway epithelium where syndecan-1 ectodomains attenuate allergic lung inflammation via suppression of CC chemokine-mediated Th2 cell recruitment to the lung.

The Future of Asthma Therapy: Integrating Clinical and Experimental Studies

Immunologic Research. 2005  |  Pubmed ID: 16120971

Asthma is one of the most common, and now most heavily investigated, of modern diseases. Research along two fronts, involving experimental models of asthma and human clinical trials, proceeds in parallel, often with investigators unaware of their counterpart's findings. Here, we review the unique immunological insights into asthma pathogenesis and therapy that may be gained from comparison of human clinical trial results and analogous experimental studies. The pitfalls and benefits of animal models of asthma are discussed, and we briefly review ongoing asthma clinical studies that are based on immunological principals. Finally, we use new insights from human and animal studies to construct a refined immunopathologic disease model that may be of use in designing future experimental and therapeutic studies.

The Role of Relaxin in Endometrial Cancer

Cancer Biology & Therapy. Jan, 2006  |  Pubmed ID: 16322684

Relaxin (RLN) is a naturally occurring hormone that is known to modulate connective tissue remodeling in the uterus and cervix. Our goal was to investigate the role of RLN in endometrial cancer. RLN expression was evaluated using immunohistochemistry in 57 samples of invasive endometrial carcinoma (EC) and ten benign endometrial tissues. 67% of high-stage (III/IV) tumors demonstrated strong RLN expression compared to 37% of low-stage (I/II) cases. Strong RLN expression associated significantly with high-grade and depth of myometrial invasion. Notably, strong RLN expression was associated with a significantly shorter overall survival (p < 0.005) compared to weak or moderate expression. Using RT-PCR, the expression of RLN and its receptor (LGR7) was detected in EC cell lines (HEC-1B and KLE); in addition, LGR7 was expressed in 86% of 15 primary EC tissue samples. Exogenous RLN stimulation caused a significant increase in migration and invasion in both cell lines, but did not stimulate proliferation in vitro. Addition of the MMP inhibitor, FN439 abolished the stimulatory effect of RLN on invasion in both HEC-1B and KLE cells. RLN stimulation caused a significant increase in levels of activated MMP-2 in KLE cells and activated MMP-9 in HEC-1B cells compared to unstimulated cells. Inhibition of endogenous RLN signaling via siRNA targeted to LGR7 caused a significant reduction of EC cell invasiveness. Our results indicate that RLN overexpression is significantly asso- ciated with aggressive features such as high-grade and deep myometrial invasion. We provide the first evidence that overexpression of RLN is associated with poor clinical outcome in women with EC. RLN stimulation enhances the invasive potential of endometrial cancer cells by upregulating MMPs. In turn, downregulation of endogenous RLN signaling decreases invasiveness of endometrial cancer cells. These novel findings may have therapeutic implications in the management of patients with endometrial carcinoma.

7. Control of Allergic Airway Inflammation Through Immunomodulation

The Journal of Allergy and Clinical Immunology. Feb, 2006  |  Pubmed ID: 16455347

Among the asthma clinical trials published over the last several years, a unique subset has focused on novel means for inhibiting the airway inflammation that is believed to cause airway obstruction in many patients. Such interventions, broadly considered here as immune-modifying or immunomodulatory therapies, include several new drugs (omalizumab, suplatast tosilate, anti-cytokine antibodies, soluble receptors, and recombinant cytokines) and bacterial extracts. In this chapter we review the major findings with these clinical trials and indicate which have changed the management of asthma, which have not, and those that deserve further study.

Identification of P311 As a Potential Gene Regulating Alveolar Generation

American Journal of Respiratory Cell and Molecular Biology. Jul, 2006  |  Pubmed ID: 16484684

Smoking-related destructive lung diseases such as chronic obstructive pulmonary disease (COPD) and emphysema are a major cause of morbidity and mortality worldwide. The immediate cause of emphysema is the obliteration of alveoli that are key functional units of the lungs where gas exchange takes place. Alveolar generation/regeneration under normal and pathologic conditions is a poorly understood process, but may hold the key to treatment of human emphysema. We used suppression subtractive hybridization to identify genes that may control alveolar generation during periods of pre- and postnatal active alveolar development. P311, a putative neuronal protein originally identified for its high expression in late-stage embryonic brain, was highly differentially expressed during periods of active distal lung morphogenesis. Quantitative real-time RT-PCR showed that the expression of P311 is developmentally regulated, with peak levels occurring during saccular and alveolar formation. Intriguingly, P311 gene expression was significantly decreased in lungs of individuals with emphysema compared with control subjects. Consistent with a role for this gene in alveolar formation, inhibition of alveolization by dexamethasone treatment in vivo resulted in decreased expression of P311. Together our data suggest that P311 expression is tightly regulated during the critical periods of alveolar formation, and that under pathologic conditions, its relative absence may contribute to failure of alveolar regeneration and lead to the development of human emphysema.

Asthma: Pathology and Pathophysiology

Archives of Pathology & Laboratory Medicine. Apr, 2006  |  Pubmed ID: 16594736

Asthma has been defined as a chronic inflammatory disorder of the airways that is associated with recruitment of inflammatory cells and the clinical development of wheezing, shortness of breath, chest tightness, and cough. Asthma is a major public health issue. It affects 5% of the United States population and accounts for 2 million emergency department visits, 470,000 hospitalizations, and 4500 deaths annually.

Proteomic Identification of in Vivo Substrates for Matrix Metalloproteinases 2 and 9 Reveals a Mechanism for Resolution of Inflammation

Journal of Immunology (Baltimore, Md. : 1950). Nov, 2006  |  Pubmed ID: 17082650

Clearance of allergic inflammatory cells from the lung through matrix metalloproteinases (MMPs) is necessary to prevent lethal asphyxiation, but mechanistic insight into this essential homeostatic process is lacking. In this study, we have used a proteomics approach to determine how MMPs promote egression of lung inflammatory cells through the airway. MMP2- and MMP9-dependent cleavage of individual Th2 chemokines modulated their chemotactic activity; however, the net effect of complementing bronchoalveolar lavage fluid of allergen-challenged MMP2(-/-)/MMP9(-/-) mice with active MMP2 and MMP9 was to markedly enhance its overall chemotactic activity. In the bronchoalveolar fluid of MMP2(-/-)/MMP9(-/-) allergic mice, we identified several chemotactic molecules that possessed putative MMP2 and MMP9 cleavage sites and were present as higher molecular mass species. In vitro cleavage assays and mass spectroscopy confirmed that three of the identified proteins, Ym1, S100A8, and S100A9, were substrates of MMP2, MMP9, or both. Function-blocking Abs to S100 proteins significantly altered allergic inflammatory cell migration into the alveolar space. Thus, an important effect of MMPs is to differentially modify chemotactic bioactivity through proteolytic processing of proteins present in the airway. These findings provide a molecular mechanism to explain the enhanced clearance of lung inflammatory cells through the airway and reveal a novel approach to target new therapies for asthma.

Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted

Physiological Reviews. Jan, 2007  |  Pubmed ID: 17237343

The matrix metalloproteinases (MMPs), a family of 25 secreted and cell surface-bound neutral proteinases, process a large array of extracellular and cell surface proteins under normal and pathological conditions. MMPs play critical roles in lung organogenesis, but their expression, for the most part, is downregulated after generation of the alveoli. Our knowledge about the resurgence of the MMPs that occurs in most inflammatory diseases of the lung is rapidly expanding. Although not all members of the MMP family are found within the lung tissue, many are upregulated during the acute and chronic phases of these diseases. Furthermore, potential MMP targets in the lung include all structural proteins in the extracellular matrix (ECM), cell adhesion molecules, growth factors, cytokines, and chemokines. However, what is less known is the role of MMP proteolysis in modulating the function of these substrates in vivo. Because of their multiplicity and substantial substrate overlap, MMPs are thought to have redundant functions. However, as we explore in this review, such redundancy most likely evolved as a necessary compensatory mechanism given the critical regulatory importance of MMPs. While inhibition of MMPs has been proposed as a therapeutic option in a variety of inflammatory lung conditions, a complete understanding of the biology of these complex enzymes is needed before we can reasonably consider them as therapeutic targets.

Type I Collagen is a Genetic Modifier of Matrix Metalloproteinase 2 in Murine Skeletal Development

Developmental Dynamics : an Official Publication of the American Association of Anatomists. Jun, 2007  |  Pubmed ID: 17440987

Recessive inactivating mutations in human matrix metalloproteinase 2 (MMP2, gelatinase A) are associated with syndromes that include abnormal facial appearance, short stature, and severe bone loss. Mmp2(-/-) mice have only mild aspects of these abnormalities, suggesting that MMP2 function is redundant during skeletal development in the mouse. Here, we report that Mmp2(-/-) mice with additional mutations that render type I collagen resistant to collagenase-mediated cleavage to TC(A) and TC(B) fragments (Col1a1(r/r) mice) have severe developmental defects resembling those observed in MMP2-null humans. Composite Mmp2(-/-);Col1a1(r/r) mice were born in expected Mendelian ratios but were half the size of wild-type, Mmp2(-/-), and Col1a1(r/r) mice and failed to thrive. Furthermore, composite Mmp2(-/-);Col1a1(r/r) animals had very abnormal craniofacial features with shorter snouts, bulging skulls, incompletely developed calvarial bones and unclosed cranial sutures. In addition, trabecular bone mass was reduced concomitant with increased numbers of bone-resorbing osteoclasts and osteopenia. In vitro, MMP2 had a unique ability among the collagenolytic MMPs to degrade mutant collagen, offering a possible explanation for the genetic interaction between Mmp2 and Col1a1(r). Thus, because mutations in the type I collagen gene alter the phenotype of mice with null mutations in Mmp2, we conclude that type I collagen is an important modifier gene for Mmp2. Developmental Dynamics 236:1683-1693, 2007. (c) 2007 Wiley-Liss, Inc.

Antielastin Autoimmunity in Tobacco Smoking-induced Emphysema

Nature Medicine. May, 2007  |  Pubmed ID: 17450149

Chronic obstructive pulmonary disease and emphysema are common destructive inflammatory diseases that are leading causes of death worldwide. Here we show that emphysema is an autoimmune disease characterized by the presence of antielastin antibody and T-helper type 1 (T(H)1) responses, which correlate with emphysema severity. These findings link emphysema to adaptive immunity against a specific lung antigen and suggest the potential for autoimmune pathology of other elastin-rich tissues such as the arteries and skin of smokers.

A New Mechanism Regulating the Initiation of Allergic Airway Inflammation

The Journal of Allergy and Clinical Immunology. Aug, 2007  |  Pubmed ID: 17544098

The earliest immune events induced by allergens are poorly understood, yet are likely essential to understanding how allergic inflammation is established.

A New Link to Airway Obstruction in Asthma

Nature Medicine. Jul, 2007  |  Pubmed ID: 17618262

Discovery of Novel Markers in Allergic Lung Inflammation Through Proteomic-based Technologies

Expert Review of Proteomics. Feb, 2008  |  Pubmed ID: 18282117

Developmental Control of Integrin Expression Regulates Th2 Effector Homing

Journal of Immunology (Baltimore, Md. : 1950). Apr, 2008  |  Pubmed ID: 18354189

Integrin CD18, a component of the LFA-1 complex that also includes CD11a, is essential for Th2, but not Th1, cell homing, but the explanation for this phenomenon remains obscure. In this study, we investigate the mechanism by which Th2 effector responses require the LFA-1 complex. CD11a-deficient T cells showed normal in vitro differentiation and function. However, Th2 cell-dependent allergic lung disease was markedly reduced in CD11a null mice and wild-type mice given LFA-1 inhibitors, whereas control of infection with Leishmania major, a Th1-dependent response, was enhanced. In both disease models, recruitment of IL-4-, but not IFN-gamma-secreting cells to relevant organs was impaired, as was adhesion of Th2 cells in vitro. These diverse findings were explained by the markedly reduced expression of CD29, an alternate homing integrin, on Th2, but not Th1, cells, which precludes Th2 homing in the absence of CD11a. Thus, murine Th1 and Th2 cells use distinct integrins for homing, suggesting novel opportunities for integrin-based therapeutic intervention in diverse human ailments influenced by Th2 cells.

Fungal Proteases Induce Th2 Polarization Through Limited Dendritic Cell Maturation and Reduced Production of IL-12

Journal of Immunology (Baltimore, Md. : 1950). May, 2008  |  Pubmed ID: 18424720

Allergens are capable of polarizing the T cell immune response toward a Th2 cytokine profile in a process that is mediated by dendritic cells (DCs). Proteases derived from Aspergillus species (Aspergillus proteases; AP) have been shown to induce a Th2-like immune response when administered directly to the airway and without adjuvant or prior priming immunizations at sites remote from the lung in models of allergic airway disease. To explore mechanisms that underlie the Th2 immune response, we have investigated the effect of AP on DC function. We found that human DCs derived from CD14(+) monocytes from healthy donors underwent partial maturation when incubated with AP. Naive allogeneic T cells primed with AP-activated DCs proliferated and displayed enhanced production of IL-4 and reduced expression of IFN-gamma as compared with naive T cells primed with LPS-activated DCs. Global gene expression analysis of DCs revealed relatively low expression of IL-12p40 in AP-activated DCs as compared with those activated by LPS, and this was confirmed at the protein level by ELISA. Exogenous IL-12p70 added to cocultures of DCs and T cells resulted in reduced IL-4 and increased IFN-gamma expression when DCs were activated with AP. When the proteolytic activity of AP was neutralized by chemical inactivation it failed to up-regulate costimulatory molecules on DCs, and these DCs did not prime a Th2 response in naive T cells. These findings provide a mechanism for explaining how proteolytically active allergens could preferentially induce Th2 responses through limited maturation of DCs with reduced production of IL-12.

A3 Adenosine Receptor Signaling Influences Pulmonary Inflammation and Fibrosis

American Journal of Respiratory Cell and Molecular Biology. Dec, 2008  |  Pubmed ID: 18587054

Adenosine is a signaling molecule produced during conditions that cause cellular stress or damage. This signaling pathway is implicated in the regulation of pulmonary disorders through the selective engagement of adenosine receptors. The goal of this study was to examine the involvement of the A(3) adenosine receptor (A(3)R) in a bleomycin model of pulmonary inflammation and fibrosis. Results demonstrated that A(3)R-deficient mice exhibit enhanced pulmonary inflammation that included an increase in eosinophils. Accordingly, there was a selective up-regulation of eosinophil-related chemokines and cytokines in the lungs of A(3)R-deficient mice exposed to bleomycin. This increase in eosinophil numbers was accompanied by a decrease in the amount of extracellular eosinophil peroxidase activity in lavage fluid from A(3)R-deficient mice exposed to bleomycin, an observation suggesting that the A(3)R is necessary for eosinophil degranulation in this model. Despite an increase in inflammatory metrics associated with A(3)R-deficient mice treated with bleomycin, there was little difference in the degree of pulmonary fibrosis. Examination of fibrotic mediators demonstrated enhanced transforming growth factor (TGF)-beta1 expression, but not a concomitant increase in TGF-beta1 activity. This was associated with the loss of expression of matrix metalloprotease 9, an activator of TGF-beta1, in alveolar macrophages and airway mast cells in the lungs of A(3)R-deficient mice. Together, these results suggest that the A(3)R serves antiinflammatory functions in the bleomycin model, and is also involved in regulating the production of mediators that can impact fibrosis.

At Last, an Immune Organ We Can Call Our Own?

American Journal of Respiratory and Critical Care Medicine. Apr, 2009  |  Pubmed ID: 19326572

Divergent Functions for Airway Epithelial Matrix Metalloproteinase 7 and Retinoic Acid in Experimental Asthma

Nature Immunology. May, 2009  |  Pubmed ID: 19329997

The innate immune response of airway epithelial cells to airborne allergens initiates the development of T cell responses that are central to allergic inflammation. Although proteinase allergens induce the expression of interleukin 25, we show here that epithelial matrix metalloproteinase 7 (MMP7) was expressed during asthma and was required for the maximum activity of interleukin 25 in promoting the differentiation of T helper type 2 cells. Allergen-challenged Mmp7(-/-) mice had less airway hyper-reactivity and production of allergic inflammatory cytokines and higher expression of retinal dehydrogenase 1. Inhibition of retinal dehydrogenase 1 restored the asthma phenotype of Mmp7(-/-) mice and inhibited the responses of lung regulatory T cells, whereas exogenous administration of retinoic acid attenuated the asthma phenotype. Thus, MMP7 coordinates allergic lung inflammation by activating interleukin 25 while simultaneously inhibiting retinoid-dependent development of regulatory T cells.

Toward a Comprehensive Understanding of Allergic Lung Disease

Transactions of the American Clinical and Climatological Association. 2009  |  Pubmed ID: 19768161

Allergic asthma is a respiratory disease induced by exposure to environmental agents that elicit allergic inflammation and transient airway obstruction and which produce the characteristic symptoms of cough and dyspnea. Prior to the advent of experimental models, asthma was believed to be caused primarily by the degranulation of mast cells and eosinophils primed by antigen-specific immunoglobulin E (IgE). More recent studies in mice have shown that T cells primarily mediate antigen-dependent airway obstruction and allergic inflammation through secretion of the cytokines interleukin 4 (IL- 4) and IL-13. Our additional studies indicate that a major environmental link to asthma may be through exposure to environmental proteinases and especially airway infection by proteinase-producing organisms such as fungi. Pending verification in humans, these findings suggest entirely new therapeutic interventions in asthma that include the restricted use of anti-inflammatory therapy and universal application of anti-fungal agents.

Smoking Gun: Mature Dendritic Cells in Human Lung Provide Clues to Chronic Obstructive Pulmonary Disease

American Journal of Respiratory and Critical Care Medicine. Dec, 2009  |  Pubmed ID: 19949238

Lung Myeloid Dendritic Cells Coordinately Induce TH1 and TH17 Responses in Human Emphysema

Science Translational Medicine. Oct, 2009  |  Pubmed ID: 20368170

Exposure to tobacco smoke activates innate and adaptive immune responses that in long-term smokers have been linked to diseases of the lungs, cardiovascular system, joints, and other organs. The destruction of lung tissue that underlies smoking-induced emphysema has been associated with T helper 1 cells that recognize the matrix protein elastin. Factors that result in the development of such autoreactive T cells in smokers remain unknown but are crucial for further understanding the pathogenesis of systemic inflammatory diseases in smokers. Here, we show that lung myeloid dendritic cells were sufficient to induce T helper 1 and T helper 17 responses in CD4 T cells. T helper 1 and 17 cells are invariably present in lungs from patients with emphysema but not in lungs from normal individuals. Interleukin-17A, a canonical T helper 17 cytokine, enhanced secretion of CCL20, a chemoattractant for dendritic cells, and matrix metalloproteinase 12, a potent elastolytic proteinase, from lung macrophages. Thus, although diverse lung factors potentially contribute to T helper effector differentiation in vivo, lung myeloid dendritic cells direct the generation of pathogenic T cells and support a feedback mechanism that sustains both inflammatory cell recruitment and lung destruction. This mechanism may underlie disease in other elastin-rich organs and tissues.

Human Rhinovirus Proteinase 2A Induces TH1 and TH2 Immunity in Patients with Chronic Obstructive Pulmonary Disease

The Journal of Allergy and Clinical Immunology. Jun, 2010  |  Pubmed ID: 20430426

Tobacco-related lung diseases, including chronic obstructive pulmonary disease (COPD), are major causes of lung-related disability and death worldwide. Acute exacerbation of COPD (AE-COPD) is commonly associated with upper and lower respiratory tract viral infections and can result in respiratory failure in those with advanced lung disease.

Proinflammatory Role for Let-7 MicroRNAS in Experimental Asthma

The Journal of Biological Chemistry. Sep, 2010  |  Pubmed ID: 20630862

MicroRNAs (miRNAs) are short, non-coding RNAs that target and silence protein coding genes through 3'-UTR elements. Evidence increasingly assigns an immunosuppressive role for miRNAs in immunity, but relatively few miRNAs have been studied, and an overall understanding of the importance of these regulatory transcripts in complex in vivo systems is lacking. Here we have applied multiple technologies to globally analyze miRNA expression and function in allergic lung disease, an experimental model of asthma. Deep sequencing and microarray analyses of the mouse lung short RNAome revealed numerous extant and novel miRNAs and other transcript classes. Similar to mRNAs, lung miRNA expression changed dynamically during the transition from the naive to the allergic state, suggesting numerous functional relationships. A possible role for miRNA editing in altering the lung mRNA target repertoire was also identified. Multiple members of the highly conserved let-7 miRNA family were the most abundant lung miRNAs, and we confirmed in vitro that interleukin 13 (IL-13), a cytokine essential for expression for allergic lung disease, is regulated by mmu-let-7a. However, inhibition of let-7 miRNAs in vivo using a locked nucleic acid profoundly inhibited production of allergic cytokines and the disease phenotype. Our findings thus reveal unexpected complexity in the miRNAome underlying allergic lung disease and demonstrate a proinflammatory role for let-7 miRNAs.

Endogenous Matrix Metalloproteinases 2 and 9 Regulate Activation of CD4+ and CD8+ T Cells

American Journal of Respiratory Cell and Molecular Biology. May, 2011  |  Pubmed ID: 20639459

We reported that inhibiting matrix metalloproteinases (MMP), known to remodel the extracellular matrix, also down-regulated antigen-specific T-cell responses. However, the direct role of MMP2 and MMP9 in regulating intracellular function in T cells is unknown. Markers of cellular activation and cytokine profiles were examined in anti-CD3-stimulated wild-type C57BL/6 mouse-derived CD4(+) or CD8(+) T cells, or MMP2- or MMP9-deficient (-/-) mice. MMP-sufficient T cells were also treated with SB-3CT, a highly selective inhibitor of MMP2 and MMP9. The effect of MMP-specific inhibition on T cell-dependent, antigen-specific murine lung injury was examined in vivo. SB-3CT induced dose-dependent reductions in anti-CD3-stimulated T-cell proliferation. Although MMP2(-/-) cells were reduced 20%, anti-CD3-induced proliferation was down-regulated 80-85% in MMP9(-/-) or in SB-3CT-treated wild-type CD4(+) and CD8(+) T cells. Intracellular calcium flux was augmented in response to MMP inhibition or deficiency in the same cells, and IL-2 production was reduced in CD4(+) and CD8(+) MMP9(-/-) T cells. SB-3CT-mediated MMP2 and MMP9 inhibition abrogated antigen-specific CD8(+) T cell-mediated lung injury in vivo. MMPs, particularly MMP9, may function intracellularly to regulate T-cell activation. T cell-targeted MMP inhibition may provide a novel approach of immune regulation in the treatment of T cell-mediated diseases.

Respiratory Tract Allergic Disease and Atopy: Experimental Evidence for a Fungal Infectious Etiology

Medical Mycology : Official Publication of the International Society for Human and Animal Mycology. Apr, 2011  |  Pubmed ID: 20807032

Allergic asthma is an obstructive lung disease linked to environmental exposures that elicit allergic airway inflammation and characteristic antigen-specific immunoglobulin reactions termed atopy. Analyses of asthma pathogenesis using experimental models have shown that T helper cells, especially T helper type 2 (Th2) cells and Th2 cytokines such as interleukin 4 (IL-4) and IL-13, are critical mediators of airway obstruction following allergen challenge, but the environmental initiators of lung Th2 responses are less defined. Our studies demonstrate that fungal-derived proteinases that are commonly found in home environments are requisite immune adjuvants capable of eliciting robust Th2 responses and allergic lung disease in mice. We have further shown that common household fungi readily infect the mouse respiratory tract and induce both asthma-like disease and atopy to otherwise innocuous bystander antigens through the secretion of proteinases. These findings support the possibility that asthma and atopy represent a reaction to respiratory tract fungal infection, suggesting novel means for diagnosis and therapy of diverse allergic disorders.

Seeking Common Pathophysiology in Asthma, Atopy and Sinusitis

Trends in Immunology. Feb, 2011  |  Pubmed ID: 21239229

Asthma and chronic sinusitis are inexplicably common airway diseases that are linked to atopy and allergic inflammation. T helper type 2 (Th2) cells and the associated cytokines are believed to play crucial pathogenic roles in asthma, but the environmental factors that instigate allergic airway disease remain poorly understood. Environmental proteinases are highly allergenic and are candidate inducers of airway Th2 responses. Determining the proteinases and their sources that are relevant to airway disease, however, remains challenging. In this Opinion, we summarize the evidence that implicates fungi as both a relevant source of allergenic proteinases and a potential cause of asthma, atopy and chronic sinusitis through airway infection. Clarification of the extrinsic causes of these processes will markedly improve diagnosis, prognosis and therapy.

Dual Protective Mechanisms of Matrix Metalloproteinases 2 and 9 in Immune Defense Against Streptococcus Pneumoniae

Journal of Immunology (Baltimore, Md. : 1950). Jun, 2011  |  Pubmed ID: 21508260

A localized and effective innate immune response to pathogenic bacterial invasion is central to host survival. Identification of the critical local innate mediators of lung defense against such pathogens is essential for a complete understanding of the mechanism(s) underlying effective host defense. In an acute model of Streptococcus pneumoniae lung infection, deficiency in matrix metalloproteinase (MMP)2 and MMP9 (Mmp2/9(-/-)) conferred a survival disadvantage relative to wild-type mice treated under the same conditions. S. pneumoniae-infected Mmp2/9(-/-) mice recruited more polymorphonuclear leukocytes to the lung but had higher bacterial burdens. Mmp2/9(-/-) mice showed significantly higher levels of IL-17A, IP-10, and RANTES in the lung. Although MMP2-dependent cleavage partially inactivated IL-17A, MMP9 was critical for effective bacterial phagocytosis and reactive oxygen species generation in polymorphonuclear neutrophils. These data demonstrate critical nonredundant and protective roles for MMP2 and MMP9 in the early host immune response against S. pneumoniae infection.

Resting Energy Expenditure and Protein Turnover Are Increased in Patients with Severe Chronic Obstructive Pulmonary Disease

Metabolism: Clinical and Experimental. Oct, 2011  |  Pubmed ID: 21550084

The mechanisms leading to weight loss in patients with chronic obstructive pulmonary disease (COPD) are poorly understood. Changes in protein metabolism and systemic inflammation may contribute to increased resting energy expenditure (REE) in COPD, leading to an energy imbalance and loss of fat and fat-free mass. The objective of this study was to determine first whether REE was increased in patients with COPD and, second, whether this was associated with increased protein turnover and/or systemic inflammation. Resting energy expenditure was determined using indirect calorimetry in 14 stable outpatients with severe COPD (7 with low and 7 with preserved body mass indices) and 7 healthy controls. Endogenous leucine flux, leucine oxidation, and nonoxidative disposal, indices of whole-body protein breakdown, catabolism, and synthesis, were measured using intravenous infusions of (13)C-bicarbonate and 1-(13)C-leucine. Total body water, from which fat-free mass and fat mass were calculated, was determined using an intravenous bolus of deuterated water. Plasma markers of systemic inflammation were also measured. As a group, subjects with COPD had increased REE adjusted for fat-free mass (P < .001) and faster rates of endogenous leucine flux (P = .006) and nonoxidative leucine disposal (P = .002) compared with controls. There was a significant correlation between REE and both endogenous leucine flux (P = .02) and nonoxidative leucine disposal (P = .008). Plasma concentrations of the inflammatory markers C-reactive protein and interleukin-6 were not different between COPD subjects and controls. Increased rates of protein turnover are associated with increased REE and loss of fat-free mass in COPD.

Cross-sectional Analysis of the Utility of Pulmonary Function Tests in Predicting Emphysema in Ever-smokers

International Journal of Environmental Research and Public Health. May, 2011  |  Pubmed ID: 21655122

Emphysema is largely an under-diagnosed medical condition that can exist in smokers in the absence of airway obstruction. We aimed to determine the sensitivity and specificity of pulmonary function tests (PFTs) in assessing emphysema using quantitative CT scans as the reference standard. We enrolled 224 ever-smokers (current or former) over the age of 40. CT of thorax was used to quantify the low attenuation area (% emphysema), and to measure the standardized airway wall thickness. PFTs were used individually and in combination to predict their ability to discriminate radiographic emphysema. Significant emphysema (>7%) was detected in 122 (54%) subjects. Twenty six (21%) emphysema subjects had no evidence of airflow obstruction (FEV(1)/FVC ratio <70%), while all subjects with >23% emphysema showed airflow obstruction. The sensitivity and specificity of spirometry for detecting radiographic emphysema were 79% and 75%, respectively. Standardized airway wall thickness was increased in subjects with airflow obstruction, but did not correlate with emphysema severity. In this cohort of lifetime ever-smokers, PFTs alone were inadequate for diagnosing emphysema. Airway wall thickness quantified by CT morphometry was associated with airflow limitation, but not with emphysema indicating that the heterogeneous nature of lung disease in smokers may represent distinct phenotypes.

Proteinases As Molecular Adjuvants in Allergic Airway Disease

Biochimica Et Biophysica Acta. Nov, 2011  |  Pubmed ID: 21712069

Asthma and related respiratory tract allergic diseases are among the most common chronic diseases of adults and children. Despite their importance, disease course cannot be predicted and treatment remains non-specific and potentially hazardous, with no means for cure. Improved clinical management of asthma will require an improved understanding of the fundamental factors that initiate allergic inflammation, especially T helper type 2 (T(H)2) cell induction.

Necessary and Sufficient Role for T Helper Cells to Prevent Fungal Dissemination in Allergic Lung Disease

Infection and Immunity. Nov, 2011  |  Pubmed ID: 21875960

Mucosal immune responses to fungal infection range from T helper type 2 (Th2) cell-directed allergic inflammation to Th1-predominant neutrophilic inflammation, but the mechanisms directing these divergent mucosal immune outcomes and the role of T cells in host defense against mucosal fungal infections are not known. Here we examined the mouse mucosal immune responses to 12 filamentous environmental fungal species over a broad range of exposure doses and determined the requirement of T cells for host defense. For all tested fungi, low-grade conidium exposures induced Th2- and eosinophil-predominant allergic lung disease, whereas higher exposures led to rapid conversion to neutrophil- and Th1 cell-predominant inflammation, a phenomenon we term immune phenotype switching. All fungal exposure doses were further linked to the secretion of interleukin-17A (IL-17A). Fungal infections with Curvularia lunata and Aspergillus fumigatus were typically confined to the airway during allergic inflammation but became locally invasive and disseminated to the brain at higher conidium challenge doses, in association with predominant Th1 responses. Fungal dissemination occurred at relatively low challenge doses with the conidia of Aspergillus fumigatus administered to recombinase activating gene 1 (Rag-1)-deficient mice, which lack B and T cells, but B cell-deficient μMT mice and T helper cell-reconstituted Rag-1-deficient mice were comparable to wild-type mice in preventing fungal dissemination. Our findings demonstrate that Th2 cell-predominant allergic responses followed by immune phenotype switching and fungal dissemination are highly predictable outcomes with progressive fungal infectious burdens and that T helper cell responses are protective against lethal fungal dissemination.

ATXN1 Protein Family and CIC Regulate Extracellular Matrix Remodeling and Lung Alveolarization

Developmental Cell. Oct, 2011  |  Pubmed ID: 22014525

Although expansion of CAG repeats in ATAXIN1 (ATXN1) causes Spinocerebellar ataxia type 1, the functions of ATXN1 and ATAXIN1-Like (ATXN1L) remain poorly understood. To investigate the function of these proteins, we generated and characterized Atxn1L(-/-) and Atxn1(-/-); Atxn1L(-/-) mice. Atxn1L(-/-) mice have hydrocephalus, omphalocele, and lung alveolarization defects. These phenotypes are more penetrant and severe in Atxn1(-/-); Atxn1L(-/-) mice, suggesting that ATXN1 and ATXN1L are functionally redundant. Upon pursuing the molecular mechanism, we discovered that several Matrix metalloproteinase (Mmp) genes are overexpressed and that the transcriptional repressor Capicua (CIC) is destabilized in Atxn1L(-/-) lungs. Consistent with this, Cic deficiency causes lung alveolarization defect. Loss of either ATXN1L or CIC derepresses Etv4, an activator for Mmp genes, thereby mediating MMP9 overexpression. These findings demonstrate a critical role of ATXN1/ATXN1L-CIC complexes in extracellular matrix (ECM) remodeling during development and their potential roles in pathogenesis of disorders affecting ECM remodeling.

Glucose and Pyruvate Metabolism in Severe Chronic Obstructive Pulmonary Disease

Journal of Applied Physiology (Bethesda, Md. : 1985). Jan, 2012  |  Pubmed ID: 22016370

The mechanisms leading to weight loss in patients with chronic obstructive pulmonary disease (COPD) are poorly understood but may involve alterations in macronutrient metabolism. Changes in muscle oxidative capacity and lactate production during exercise suggest glucose metabolism may be altered in COPD subjects. The objective of this study was to determine differences in the rates of glucose production and clearance, the rate of glycolysis (pyruvate production), and oxidative and nonoxidative pyruvate disposal in subjects with severe COPD compared with healthy controls. The in vivo rates of glucose production and clearance were measured in 14 stable outpatients with severe COPD (seven with low and seven with preserved body mass indexes) and 7 healthy controls using an intravenous infusion of [(2)H(2)]glucose. Additionally, pyruvate production and oxidative and non-oxidative pyruvate disposal were measured using intravenous infusions of [(13)C]bicarbonate and [(13)C]pyruvate. Endogenous glucose flux and glucose clearance were significantly faster in the combined COPD subjects (P = 0.002 and P < 0.001, respectively). This difference remained significant when COPD subjects were separated by body mass index. Pyruvate flux and oxidation were significantly higher in the combined COPD subjects than controls (P = 0.02 for both), but there was no difference in nonoxidative pyruvate disposal or plasma lactate concentrations between the two groups. In subjects with severe COPD, there are alterations in glucose metabolism leading to increased glucose production and faster glucose metabolism by glycolysis and oxidation compared with controls. However, no difference in glucose conversion to lactate via pyruvate reduction is observed.

Cigarette Smoke Induction of Osteopontin (SPP1) Mediates TH17 Inflammation in Human and Experimental Emphysema

Science Translational Medicine. Jan, 2012  |  Pubmed ID: 22261033

Smoking-related lung diseases are among the leading causes of death worldwide, underscoring the need to understand their pathogenesis and develop new effective therapies. We have shown that CD1a(+) antigen-presenting cells (APCs) from lungs of patients with emphysema can induce autoreactive T helper 1 (T(H)1) and T(H)17 cells. Similarly, the canonical cytokines interferon-γ (IFN-γ) and interleukin-17A (IL-17A) are specifically linked to lung destruction in smokers, but how smoke activates APCs to mediate emphysema remains unknown. Here, we show that, in addition to increasing IFN-γ expression, cigarette smoke increased the expression of IL-17A in both CD4(+) and γδ T cells from mouse lung. IL-17A deficiency resulted in attenuation of, whereas lack of γδ T cells exacerbated, smoke-induced emphysema in mice. Adoptive transfer of lung APCs isolated from mice with emphysema revealed that this cell population was capable of transferring disease even in the absence of active smoke exposure, a process that was dependent on IL-17A expression. Spp1 (the gene for osteopontin) was highly expressed in the pathogenic lung APCs of smoke-exposed mice and was required for the T(H)17 responses and emphysema in vivo, in part through its inhibition of the expression of the transcription factor Irf7. Thus, the Spp1-Irf7 axis is critical for induction of pathological T(H)17 responses, revealing a major mechanism by which smoke activates lung APCs to induce emphysema and identifying a pathway that could be targeted for therapeutic purposes.