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MCP-Induced Protein 1 Participates in Macrophage-Dependent Endotoxin Tolerance
Marta Wadowska1, Ewelina Dobosz2, Anna Golda1
1Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, Krakow, Poland.
Journal of Immunology (Baltimore, Md. : 1950)
|September 27, 2022
Summary
MCP-induced protein 1 (MCPIP1) regulates endotoxin tolerance by inhibiting key inflammatory pathways. This discovery identifies MCPIP1 as a novel negative regulator of Toll-like receptor signaling, crucial in sepsis and infection risk.
Area of Science:
- Immunology
- Molecular Biology
- Cellular Biology
Background:
- Endotoxin tolerance, a hyporesponsive state to lipopolysaccharide (LPS), increases secondary infection risk and is linked to sepsis pathophysiology.
- The precise molecular mechanisms underlying endotoxin tolerance remain incompletely understood.
- Negative regulators of Toll-like receptor (TLR) signaling are implicated, but the role of MCP-induced protein 1 (MCPIP1; Regnase-1) is unexplored.
Purpose of the Study:
- To investigate the role of macrophage MCPIP1 expression in the development of endotoxin tolerance.
- To elucidate the molecular mechanisms by which MCPIP1 influences LPS hyporesponsiveness.
Main Methods:
- Utilized murine and human primary macrophages lacking MCPIP1 expression.
- Assessed MAPK and NF-κB activation pathways.
- Analyzed proinflammatory transcript levels.
- Employed an in vivo endotoxin tolerance model in wild-type and MCPIP1-deficient mice.
Main Results:
- MCPIP1 deficiency abrogated LPS-induced hyporesponsiveness and macrophage reprogramming.
- MCPIP1's deubiquitinase activity was essential for inhibiting MAPK phosphorylation and NF-κB activation.
- MCPIP1 regulated proinflammatory transcripts in tolerized cells independently of its RNase activity.
- In vivo studies confirmed MCPIP1's critical role in endotoxin tolerance.
Conclusions:
- Myeloid MCPIP1 is a novel and significant participant in endotoxin tolerance.
- MCPIP1 acts as a negative regulator of TLR4 signaling, impacting sepsis and infection.
- The deubiquitinase activity of MCPIP1 is key to its function in this process.
