Oligomeric S100A4 Is Associated With Monocyte Innate Immune Memory and Bypass of Tolerance to Subsequent Stimulation With Lipopolysaccharides

Conclusion: Bypass of tolerance by DAMPs might be a phenomenon as important as TI, since it could explain how chronic inflammation can be maintained in spite of an environment with multiple TLR2/TLR4-ligands. In RA monocytes, a PRDM8-dependent TI mechanism could be responsible for sustained chemokine/cytokines levels. Introduction Monocytes and macrophages play a central role in the pathophysiology of inflammation. For instance, in rheumatoid arthritis (RA), activated monocytes massively infiltrate synovial tissues and produce tumor necrosis factor-α (TNFα) (1–3). Accordingly, therapies aimed at blocking this cytokine have emerged as a major tool in the treatment of RA and other inflammatory diseases (4, 5). These observations indicate the essential role of TNFα in the pathogenesis of RA. Indeed, RA synovial fibroblasts have an intrinsic ability to destroy cartilage and bone due to epigenetic changes (6), and TNFα further stimulates their aggressive behavior (7). Abnormal activation of pattern recognition receptors (PRRs), like Toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE) by endogenous danger signals (damage-associated molecular patterns; DAMPs) as well as infectious agents (pathogen-associated molecular patterns; PAMPs) has been suggested to be crucial for perpetuating vicious inflammatory cycles (8–10). In RA, of special interest is the oligomeric form of S100A4 (oS100A4), which ...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research