in-vivo-imaging-uncovers-migratory-behavior-leukocytes-within

<em>In Vivo</em> Imaging Uncovers the Migratory Behavior of Leukocytes within the Joints

Leukocytes are blood-borne cells derived from the bone marrow that must migrate into tissues to mediate inflammation. Controlling this migration, ...

St. Marianna University School of Medicine

Nephritis-associated plasmin receptor in the cutaneous vessels in IgA vasculitis.

Rheumatoid arthritis (RA) is an autoimmune disease that commonly causes inflammation and bone destruction in multiple joints. Inflammatory cytokines, such as IL-6 and TNF-α, play important roles in RA development and pathogenesis. Biological therapies targeting these cytokines have revolutionized RA therapy. However, approximately 50% of the patients are non-responders to these therapies. Therefore, there is an ongoing need to identify new therapeutic targets and therapies for patients with RA. In this review, we focus on the pathogenic roles of chemokines and their G-protein-coupled receptors (GPCRs) in RA. Inflamed tissues in RA, such as the synovium, highly express various chemokines to promote leukocyte migration, tightly controlled by chemokine ligand-receptor interactions. Because the inhibition of these signaling pathways results in inflammatory response regulation, chemokines and their receptors could be promising targets for RA therapy. The blockade of various chemokines and/or their receptors has yielded prospective results in preclinical trials using animal models of inflammatory arthritis. However, some of these strategies have failed in clinical trials. Nonetheless, some blockades showed promising results in early-phase clinical trials, suggesting that chemokine ligand-receptor interactions remain a promising therapeutic target for RA and other autoimmune diseases.

Chemokines and chemokine receptors as promising targets in rheumatoid arthritis.

Vasculitis is a systemic autoimmune disease characterized by leukocyte infiltration into blood vessels. Various microorganisms have been associated with the pathogenesis of vasculitis; however, the causal microbial agents and underlying mechanisms are not fully understood, possibly because of the technical limitations of pathogen detection. In the present study, we characterized the microbiome profile of patients with cutaneous vasculitis using comprehensive metagenome shotgun sequencing. We found that the abundance of the SEN virus was increased in the affected skin and serum of patients with vasculitis compared to healthy donors. In particular, the abundance of SEN virus reads was increased in the sera of patients with cutaneous arteritis. Among the bacteria identified, Corynebacteriales was the most differentially associated with vasculitis. Linear discriminant analysis effect size also indicated differences in the microbial taxa between patients with vasculitis and healthy donors. These findings demonstrate that vasculitis is associated with considerable alteration of the microbiome in the blood and skin and suggest a role for the infectious trigger in vasculitis.

Alteration of microbial composition in the skin and blood in vasculitis.

Excessive activation of immune cells by environmental factors, such as infection or individual genetic risk, causes various autoimmune diseases.  species are gram-positive bacteria that colonize the nasopharynx, respiratory tract, gastrointestinal tract, genitourinary tract, and skin. Group A  (GAS) species cause various symptoms, ranging from mild infections, such as tonsillitis and pharyngitis, to serious infections, such as necrotizing fasciitis and streptococcal toxic shock syndrome. The contribution of GAS infections to several autoimmune diseases, including acute rheumatic fever, vasculitis, and neuropsychiatric disorders, has been studied. In this review, we focus on the association between streptococcal infections and autoimmune diseases, and discuss current research on the mechanisms underlying the initiation and progression of autoimmune diseases.

Streptococcal infection and autoimmune diseases.

The tumor microenvironment (TME) impacts the therapeutic efficacy of immune checkpoint inhibitors (ICIs). No liquid biomarkers are available to evaluate TME heterogeneity. Here, we investigated the clinical significance of PD-1-binding soluble PD-L1 (bsPD-L1) in gastric cancer (GC) patients and non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 blockade.

Combination of plasma MMPs and PD-1-binding soluble PD-L1 predicts recurrence in gastric cancer and the efficacy of immune checkpoint inhibitors in non-small cell lung cancer.

 Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs). Liquid biomarkers to predict irAE occurrence are urgently needed. We previously developed an ELISA system to specifically detect soluble PD-L1 (sPD-L1) with PD-1-binding capacity (bsPD-L1). Here, we investigated the relationship between sPD-L1 and bsPD-L1 in gastric cancer (GC) and non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 blockade and their association with irAEs.  We examined sPD-L1, bsPD-L1, matrix metalloproteinases (MMPs), and proinflammatory cytokine levels by ELISA in plasma samples from 117 GC patients prior to surgery and 72 NSCLC patients prior to and at 2 months after ICI treatment (anti-PD-1, n = 48; anti-PD-L1, n = 24). In mice treated with anti-PD-1/PD-L1 antibodies (Abs), sPD-L1 levels and localization of Abs were examined by ELISA and immunohistochemistry, respectively. sPD-L1 was detected with higher frequency in GC patients than in NSCLC patients, whereas bsPD-L1 was detected with similar frequencies in GC and NSCLC patients. sPD-L1 levels were correlated with IL-1α, IL-1β, TNF-α, and IL-6 levels, while bsPD-L1 levels were correlated with MMP13, MMP3, and IFN-γ levels. In NSCLC patients, anti-PD-L1, but not anti-PD-1, treatment increased sPD-L1, which was associated with irAE development, but not with clinical outcomes. In mice, trafficking of anti-PD-L1 Abs to lysosomes in F4/80 macrophages resulted in sPD-L1 production, which was suppressed by treatment with lysosomal degradation inhibitor chloroquine and macrophage depletion.  Anti-PD-L1-mediated lysosomal degradation induces sPD-L1 production, which can serve as an indicator to predict irAE development during anti-PD-L1 treatment.

Lysosomal degradation of PD-L1 is associated with immune-related adverse events during anti-PD-L1 immunotherapy in NSCLC patients.

The dense nerve and thin vascular structure of the corneal tissue provide the refractive function in healthy eyes. Diabetes mellitus causes ocular complications including corneal opacification because of corneal nerve degeneration. Diabetic neurotrophic keratopathy is characterized by reduced corneal sensitivity, delayed corneal wound healing, and nerve degeneration. Neurotization and vascularization inhibit each other in the cornea. Macrophages contribute to the corneal neovascularization. To investigate the role of macrophage in neurotrophic keratopathy, clodronate liposome was subconjunctivally injected into diabetic db/db mice with neurotrophic keratopathy. The clodronate liposome treatment decreased F4/80 macrophage infiltration into the corneal epithelium, and improved corneal nerve involvement in diabetic db/db mice. Furthermore, we found that Il1b and Il34 mRNA expression was increased in the corneal epithelium of clodronate-treated diabetic db/db mice. These cytokines contribute to the maintenance of nerve tissues via microglia and nerve regeneration; however, their role in corneal nerve involvement remains unknown. Notably, the intraocular injection of recombinant IL-1β and IL-34 promoted nerve regeneration in the cornea of diabetic db/db mice. These results suggest that clodronate liposome treatment contributes to nerve regeneration during corneal involvement via IL-1β and IL-34 signaling.

Clodronate liposome treatment contributes to the nerve regeneration in corneal nerve involvement of diabetic mice.

Ménière's disease (MD) is characterized by loss of balance and hearing disorders. Although there is known to be endolymphatic hydrops involved in the pathological process, the pathogenesis of the disease is still largely unclear. Approximately half of patients with MD suffer from depressive symptoms and high levels of several stress hormones were observed in MD and depression, simultaneously. Recently, gut microbes have been shown to influence the function of the central nervous system in humans through their metabolites. We studied the intestinal microbiota of 10 patients with MD and 11 healthy donors (HD). Significant negative correlations were found between disease duration and alpha diversity indexes of gut microbes in patients with MD. The relative abundance of the species Butyricicoccus ambiguous taxa was increased in patients with MD compared with that of HD. In contrast, Oscillospiraceae UCG-002/UCG-005 ambiguous taxa and Anaerovoracaceae (Eubacterium) brachy group uncultured bacterium were increased in the relative abundance of HD than that of patients with MD. The relative abundance of the Butyricicoccus species was positively correlated with disease duration. Thus, these compositional alterations of gut microbes in patients with MD are associated with inner ear pathologies, such as endolymphatic hydrops, by changing the metabolite profiles in the intestine.

Article	Year
Nephritis-associated plasmin receptor in the cutaneous vessels in IgA vasculitis. The Journal of dermatology\| PubMed ID: 36151872	2023
Chemokines and chemokine receptors as promising targets in rheumatoid arthritis. Frontiers in immunology\| PubMed ID: 36860872	2023
Alteration of microbial composition in the skin and blood in vasculitis. Scientific reports\| PubMed ID: 37714908	2023
Streptococcal infection and autoimmune diseases. Frontiers in immunology\| PubMed ID: 38464518	2024
Combination of plasma MMPs and PD-1-binding soluble PD-L1 predicts recurrence in gastric cancer and the efficacy of immune checkpoint inhibitors in non-small cell lung cancer. Frontiers in pharmacology\| PubMed ID: 38774209	2024
Lysosomal degradation of PD-L1 is associated with immune-related adverse events during anti-PD-L1 immunotherapy in NSCLC patients. Frontiers in pharmacology\| PubMed ID: 38799168	2024
Clodronate liposome treatment contributes to the nerve regeneration in corneal nerve involvement of diabetic mice. Experimental animals\| PubMed ID: 39111878	2025
Microbial alpha diversity in the intestine negatively correlated with disease duration in patients with Meniere's disease. Scientific reports\| PubMed ID: 39738510	2024

Yoshishige Miyabe

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