Abstract
Myeloid-related protein 8 (Mrp8) is the active component of Mrp8/14 protein complex released by phagocytes at the site of infection and stimulates inflammatory responses. However, it is unclear whether Mrp8 could induce self-tolerance and cross-tolerance to bacterial infection. Here we report that Mrp8 triggered TNF-α and IL-6 release via a Toll-like receptor 4 (TLR4)-dependent manner. Pre-stimulation of murine macrophages and human monocytes with Mrp8 induced self-tolerance to Mrp8 re-stimulation and cross-tolerance to lipopolysaccharide (LPS), bacterial lipoprotein (BLP), gram-negative and gram-positive bacterial challenges, with substantially attenuated TNF-α and IL-6 release. Moreover, Mrp8 tolerisation significantly reduced serum TNF-α and IL-6, increased polymorphonuclear neutrophil (PMN) recruitment and accelerated bacterial clearance, thus protecting mice against LPS-induced lethality and cecal ligation and puncture (CLP)-induced polymicrobial sepsis. In addition to TLR4, TLR2 also contributed to Mrp8-induced inflammatory response and tolerance. Down-regulation of phosphorylated p38 by Mrp8 pre-stimulation was predominantly responsible for the intracellular mechanism of Mrp8-induced tolerance. Thus, our findings of Mrp8-induced self-tolerance and cross-tolerance may provide a potential strategy for attenuating an overwhelming proinflammatory cascade and enhancing antimicrobial responses during microbial sepsis.
Highlights
The S100 proteins represent a group of more than twenty calcium-binding proteins, and three of which, known as myeloid-related proteins (Mrps) or calgranulins, have been linked to innate immune functions by their expression on myeloid cells
The Mrp8/14 complex induces a variety of inflammatory reactions and the level of Mrp8/14 expression correlates with disease activity in several autoimmune inflammatory disorders including rheumatoid arthritis, SLE and inflammatory bowel disease, and is elevated during infection[13,15,16]
Stimulation of naïve murine peritoneal macrophages (Fig. 1A) or bone marrow-derived macrophages (BMMs) (Fig. 1B) with murine Mrp[8] for 6 h caused an inflammatory response quantified by significant release of TNF-α and IL-6 compared with macrophages incubated with culture medium alone
Summary
The S100 proteins represent a group of more than twenty calcium-binding proteins, and three of which, known as myeloid-related proteins (Mrps) or calgranulins, have been linked to innate immune functions by their expression on myeloid cells. The Mrp8/14 complex induces a variety of inflammatory reactions and the level of Mrp8/14 expression correlates with disease activity in several autoimmune inflammatory disorders including rheumatoid arthritis, SLE and inflammatory bowel disease, and is elevated during infection[13,15,16]. An increased inflammatory response may represent more of a danger to the host rather than protection against bacterial infection, as seen in the setting of septic shock. This was confirmed when Mrp14-deficient mice showed an improved survival after the intraperitoneal injection of live E. coli[7]. In the present study we attempted to investigate the potential role of Mrp[8] in inducing self-tolerance and cross-tolerance to bacterial infection
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