MCP-Induced Protein 1 Participates in Macrophage-Dependent Endotoxin Tolerance [INNATE IMMUNITY AND INFLAMMATION]

Key Points

Myeloid MCPIP1 controls the endotoxin tolerance.

MCPIP1 ensures the tolerance to LPS via restriction of the NF-κB signaling pathway.

MCPIP1 determines endotoxin tolerance independently of its RNase activity.

Abstract

Endotoxin tolerance is a state of hyporesponsiveness to LPS, triggered by previous exposure to endotoxin. Such an immunosuppressive state enhances the risks of secondary infection and has been associated with the pathophysiology of sepsis. Although this phenomenon has been extensively studied, its molecular mechanism is not fully explained. Among candidates that play a crucial role in this process are negative regulators of TLR signaling, but the contribution of MCP-induced protein 1 (MCPIP1; Regnase-1) has not been studied yet. To examine whether macrophage expression of MCPIP1 participates in endotoxin tolerance, we used both murine and human primary macrophages devoid of MCPIP1 expression. In our study, we demonstrated that MCPIP1 contributes to LPS hyporesponsiveness induced by subsequent LPS stimulation and macrophage reprogramming. We proved that this mechanism revolves around the deubiquitinase activity of MCPIP1, which inhibits the phosphorylation of MAPK and NF-κB activation. Moreover, we showed that MCPIP1 controlled the level of proinflammatory transcripts in LPS-tolerized cells independently of its RNase activity. Finally, we confirmed these findings applying an in vivo endotoxin tolerance model in wild-type and myeloid MCPIP1–deficient mice. Taken together, this study describes for the first time, to our knowledge, that myeloid MCPIP1 participates in endotoxin tolerance and broadens the scope of known negative regulators of the TLR4 pathway crucial in this phenomenon.

Footnotes

This work was supported by National Science Center, Poland (Grants UMO-2011/03/B/NZ6/00053 and UMO-2018/29/B/NZ6/01622 to J.K.). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The online version of this article contains supplemental material.

J.K., M.W., and E.D. designed experiments and supervised data analysis; M.W., E.D., A.G., D.B., and J.K. performed experiments with human and murine cells and analyzed data; M.W., A.G., M.L., and J.K. conducted in vivo experiments; M.W., E.D., and J.K. planned and supervised the project; M.F. provided resources; M.W., E.D., and J.K. prepared the original draft. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Abbreviations used in this article:

AF488Alexa Fluor 488BMDMbone marrow–derived macrophageCmControl mutantCRPC-reactive proteinCtthreshold cyclehMDMhuman monocyte-derived macrophageIRAKIL-1R–associated kinaseLysMcre+MCPIP1-LysMcre+MCPIP1MCP-induced protein 1MPOmyeloperoxidaseqPCRquantitative PCRWTwild-typeReceived December 17, 2021.Accepted July 28, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.

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