Christoph Kessel

Proinflammatory S100A12 Can Activate Human Monocytes via Toll-like Receptor 4

RATIONALE 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. OBJECTIVES We analyzed the activation of human monocytes by granulocyte-derived S100A12 as a key function of early inflammatory processes and the development of sepsis. METHODS Circulating S100A12 was determined in patients with sepsis and in healthy subjects with experimental endotoxemia. The release of human S100A12 from granulocytes as well as the promotion of inflammation by activation of human monocytes after specific receptor interaction was investigated by a series of in vitro experiments. MEASUREMENTS AND MAIN RESULTS S100A12 rises during sepsis, and its expression and release from granulocytes is rapidly induced in vitro and in vivo by inflammatory challenge. A global gene expression analysis of S100A12-activated monocytes revealed that human S100A12 induces inflammatory gene expression. These effects are triggered by an interaction of S100A12 with Toll-like receptor 4 (TLR4). Blocking S100A12 binding to TLR4 on monocytes or TLR4 expressing cell lines (HEK-TCM) abrogates the respective inflammatory signal. On the contrary, blocking S100A12 binding to its second proposed receptor (receptor for advanced glycation end products [RAGE]) has no significant effect on inflammatory signaling in monocytes and RAGE-expressing HEK293 cells. CONCLUSIONS Human S100A12 is an endogenous TLR4 ligand that induces monocyte activation, thereby acting as an amplifier of innate immunity during early inflammation and the development of sepsis.

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

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.

Pro-inflammatory cytokine environments can drive IL-17 over-expression by γδT cells in systemic juvenile idiopathic arthritis

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.

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

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.

Secretory Activity of Neutrophils Correlates With Genotype in Familial Mediterranean Fever

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.

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

S100A12 is highly overexpressed in certain autoinflammatory diseases. Here we describe, that upon cellular release Ca2+ and Zn2+ can operate as molecular switch rendering S100A12 into a toll-like receptor 4-ligand to trigger sterile inflammation.

Hexameric S100A12 is required for pro-inflammatory TLR4-signalling

The human granulocyte-specific Ca2+-binding protein S100A12 is particularily over-expressed in autoinflammatory diseases such as juvenile idiopathic arthritis (JIA) as well as other inflammatory conditions (i.e. infections, vasculitides) and has been ascribed to the group of pro-inflammatory damage associated molecular pattern molecules (DAMPs). In order to operate as DAMP, S100A12 requires binding to cellular receptors. Although the protein was originally found to bind the receptor of advanced glycation endproducts (RAGE), we recently demonstrated S100A12 to stimulate proinflammatory cytokine production in monocytes via TLR4 instead of RAGE.

OR6-001 - S100A12 as pro-inflammatory TLR4 ligand

The granulocyte-specific Ca2+-binding protein S100A12 is overexpressed during autoinflammation as well as other inflammatory conditions in humans and has been ascribed to the group of pro-inflammatory Damage Associated Molecular Pattern molecules (DAMPs). S100A12-levels in human serum reveal excellent correlation with patients’ inflammation state, which renders S100A12 a powerful biomarker. In order to operate as DAMP S100A12 requires binding to cellular receptors. The protein was originally found to bind RAGE and was in turn entitled extracellular newly identified RAGE-binding protein (EN-RAGE). RAGE ligation by S100A12 is proposed to trigger a pro-inflammatory cascade in microvascular endothelial cells, macrophages and lymphocytes, culminating in NFκ-B activation. This amplifies the inflammatory response by triggering further RAGE expression and thus drives a feed-forward loop that can potentiate inflammation.

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

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.

PReS-FINAL-2340: A pathogenic role for S100A8/A9 in experimental autoimmune arthritis

Damage Associated Molecular Pattern molecules (DAMPs) like HMGB1 have been demonstrated to be involved in pathological processes triggering and perpetuating autoimmune arthritis by attraction and activation of immune cells. The phagocyte-specific S100 proteins A8 and A9 (Myeloid Related Protein 8 and 14, respectively) are expressed by monoyctes and granulocytes and can likewise operate as DAMPs by signalling through TLR4 once released into the extracellular space.