Myeloid-related protein 8 induces self-tolerance and cross-tolerance to bacterial infection via TLR4- and TLR2-mediated signal pathways.
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.
Department of Academic Surgery, University College Cork/National University of Ireland, Cork University Hospital, Cork, Ireland.
Andrew P
AP
Coveney
Department of Academic Surgery, University College Cork/National University of Ireland, Cork University Hospital, Cork, Ireland.|Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
Wei
W
Wang
Department of Academic Surgery, University College Cork/National University of Ireland, Cork University Hospital, Cork, Ireland.
Justin
J
Kelly
Department of Academic Surgery, University College Cork/National University of Ireland, Cork University Hospital, Cork, Ireland.|Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
Jing Hua
JH
Liu
Department of Academic Surgery, University College Cork/National University of Ireland, Cork University Hospital, Cork, Ireland.
Siobhan
S
Blankson
Department of Academic Surgery, University College Cork/National University of Ireland, Cork University Hospital, Cork, Ireland.
Qiong Di
QD
Wu
Department of Academic Surgery, University College Cork/National University of Ireland, Cork University Hospital, Cork, Ireland.
H Paul
HP
Redmond
Department of Academic Surgery, University College Cork/National University of Ireland, Cork University Hospital, Cork, Ireland.
Jiang Huai
JH
Wang
D000818:Animals; D001424:Bacterial Infections / Q000276:immunology* / Q000378:metabolism*; D040501:Calgranulin A / Q000378:metabolism*; D002432:Cecum / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D008026:Ligation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008074:Lipoproteins / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*; D011677:Punctures; D018805:Sepsis / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D040501:Calgranulin A; D008070:Lipopolysaccharides; D008074:Lipoproteins; D016328:NF-kappa B; D011506:Proteins; C086145:S100a8 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases