purification-human-s100a12-its-ion-induced-oligomers-for-immune-cell

Purification of Human S100A12 and Its Ion-induced Oligomers for Immune Cell Stimulation

In this protocol, we describe a method to purify human calcium-binding protein S100A12 and its ion-induced oligomers from Escherichia coli culture for ...

University Children's Hospital

The cytoplasmic S100 proteins derived from cells of myeloid origin are promising new markers of (auto-)inflammation. S100A8/A9 and S100A12 are released from monocytes and granulocytes during activation of the innate immune system. Tissue and serum concentrations correlate to disease activity, both during local and systemic inflammation. In autoinflammatory diseases such as Familial Mediterranean Fever (FMF) and Systemic onset Juvenile Idiopathic Arthritis (SJIA), a dysregulation of alternative secretory pathways may be involved in pathogenesis and lead to hypersecretion of S100 proteins. Since autoinflammatory diseases can be difficult to diagnose, phagocyte-derived S100 proteins are valid tools in the diagnosis of autoinflammatory diseases. In addition, they may help achieve a better understanding of the pathophysiology of autoinflammatory disorders including SJIA and FMF, and even provide novel therapeutic targets in the future.

Phagocyte-derived S100 proteins in autoinflammation: putative role in pathogenesis and usefulness as biomarkers.

S100A12 is overexpressed during inflammation and is a marker of inflammatory disease. Furthermore, it has been ascribed to the group of damage-associated molecular pattern molecules that promote inflammation. However, the exact role of human S100A12 during early steps of immune activation and sepsis is only partially described thus far.

Proinflammatory S100A12 can activate human monocytes via Toll-like receptor 4.

Translational research approaches brought major changes to the understanding and treatment options of autoinflammatory diseases. Patients with common complex multifactorial diseases such as systemic-onset juvenile idiopathic arthritis (sJIA), and particularly those with rare monogenic autoinflammatory diseases such as cryopyrin-associated periodic syndromes (CAPS) or TNF receptor-associated periodic syndrome (TRAPS), benefited from a deeper understanding of the pathophysiological mechanisms and new treatment options emerging from preclinical studies. The study of IL-1 and IL-6 in this context led to novel therapies by forward translation. Conversely, effective treatment of sJIA and TRAPS with IL-1 blockade stimulated reverse translational efforts to study the pathophysiology of these cytokines in autoinflammatory diseases. These translational efforts led to the discovery of biomarkers such as S100 proteins, IL-18 or serum amyloid A, which are components of the inflammatory process, support diagnosis and allow for monitoring of disease activity, helping to predict patient outcomes. The ongoing characterization of autoinflammatory diseases in individual patients has led to classification into heterogeneous subgroups. Further characterization of relevant subgroups and the design of tailored treatment regimens, as well as the identification of new therapeutic targets and treatment options, are the major future challenges in the field of autoinflammatory diseases, particularly for paediatric rheumatologists. 

From bench to bedside and back again: translational research in autoinflammation.

Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin-encoding MEFV mutations. Patients present with recurrent but self-limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil-derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF.

Correlation of Secretory Activity of Neutrophils With Genotype in Patients With Familial Mediterranean Fever.

Systemic-onset juvenile idiopathic arthritis (JIA) is speculated to follow a biphasic course, with an initial systemic disease phase driven by innate immune mechanisms and interleukin-1β (IL-1β) as a key cytokine and a second chronic arthritic phase that may be dominated by adaptive immunity and cytokines such as IL-17A. Although a recent mouse model points to a critical role of IL-17-expressing γ/δ T cells in disease pathology, in humans, both the prevalence of IL-17 and the role of IL-17-producing cells are still unclear.

Proinflammatory Cytokine Environments Can Drive Interleukin-17 Overexpression by γ/δ T Cells in Systemic Juvenile Idiopathic Arthritis.

Calcium and zinc tune autoinflammatory Toll-like receptor 4 signaling by S100A12.

S100A8/A9 and S100A12 are released from activated monocytes and granulocytes and act as proinflammatory endogenous toll-like receptor (TLR)4-ligands. S100 serum concentrations correlate with disease activity, both during local and systemic inflammatory processes. In some autoinflammatory diseases such as familial Mediterranean fever (FMF) or systemic juvenile idiopathic arthritis (SJIA), dysregulation of S100 release may be involved in the pathogenesis. Moreover, S100 serum levels are a valuable supportive tool in the diagnosis of SJIA in fever of unknown origin. Furthermore, S100 levels can be used to monitor disease activity to subclinical level, as their serum concentrations decrease with successful treatment.

The role of S100 proteins in the pathogenesis and monitoring of autoinflammatory diseases.

Kawasaki disease (KD) is an acute vasculitis of childhood, predominantly affecting the coronary arteries. S100A12, a granulocyte-derived agonist of both the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR-4), is strongly up-regulated in KD. This study was undertaken to investigate the potential contributions of S100A12 to the pathogenesis of KD.

Monocyte-Derived Interleukin-1β As the Driver of S100A12-Induced Sterile Inflammatory Activation of Human Coronary Artery Endothelial Cells: Implications for the Pathogenesis of Kawasaki Disease.

Article	Year
Phagocyte-derived S100 proteins in autoinflammation: putative role in pathogenesis and usefulness as biomarkers. Clinical immunology (Orlando, Fla.)\| PubMed ID: 23269200	2013
Proinflammatory S100A12 can activate human monocytes via Toll-like receptor 4. American journal of respiratory and critical care medicine\| PubMed ID: 23611140	2013
From bench to bedside and back again: translational research in autoinflammation. Nature reviews. Rheumatology\| PubMed ID: 26077920	2015
Correlation of Secretory Activity of Neutrophils With Genotype in Patients With Familial Mediterranean Fever. Arthritis & rheumatology (Hoboken, N.J.)\| PubMed ID: 27333294	2016
Proinflammatory Cytokine Environments Can Drive Interleukin-17 Overexpression by γ/δ T Cells in Systemic Juvenile Idiopathic Arthritis. Arthritis & rheumatology (Hoboken, N.J.)\| PubMed ID: 28296284	2017
Calcium and zinc tune autoinflammatory Toll-like receptor 4 signaling by S100A12. The Journal of allergy and clinical immunology\| PubMed ID: 30010542	2018
The role of S100 proteins in the pathogenesis and monitoring of autoinflammatory diseases. Molecular and cellular pediatrics\| PubMed ID: 30255357	2018
Monocyte-Derived Interleukin-1β As the Driver of S100A12-Induced Sterile Inflammatory Activation of Human Coronary Artery Endothelial Cells: Implications for the Pathogenesis of Kawasaki Dis... Arthritis & rheumatology (Hoboken, N.J.)\| PubMed ID: 30447136	2019

Christoph Kessel

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