MCPIP-1 Restricts Inflammation via Promoting Apoptosis of Neutrophils.

Ewelina Dobosz,Joanna Koziel,Jan Potempa,Mohsen Honarpisheh,Maciej Lech,Jolanta Jura,Mateusz Wilamowski,Marta Wadowska,Danuta Bryzek,Marta Kaminska

doi:10.3389/fimmu.2021.627922

Abstract

Monocyte chemoattractant protein-induced protein-1 (MCPIP-1) is a potent inhibitor of inflammatory response to pathogens. Acting as endonuclease against transcripts of inflammatory cytokines or transcription factors MCPIP-1 can significantly reduce the cytokine storm, thus limiting the tissue damage. As the adequate resolution of inflammation depends also on the efficient clearance of accumulated neutrophils, we focused on the role of MCPIP-1 in apoptosis and retention of neutrophils. We used peritoneal neutrophils from cell-specific MCPIP-1 knockout mice and showed prolonged survival of these cells. Moreover, we confirmed that MCPIP-1-dependent degradation of transcripts of antiapoptotic genes, including BCL3, BCL2A1, BCL2L1, and for the first time MCL-1, serves as an early event in spontaneous apoptosis of primary neutrophils. Additionally, we identified previously unknown miRNAs as potential binding partners to the MCPIP-1 transcript and their regulation suggest a role in MCPIP-1 half-life and translation. These phenomena may play a role as a molecular switch that balances the MCPIP-1-dependent apoptosis. Besides that, we determined these particular miRNAs as integral components of the GM-CSF-MCPIP-1 axis. Taken together, we identified the novel anti-inflammatory role of MCPIP-1 as a regulator of accumulation and survival of neutrophils that simultaneously promotes an adequate resolution of inflammation.

Highlights

Monocyte chemoattractant protein-induced protein-1 (MCPIP-1), called Regnase-1, is a potent negative regulator of the inflammatory response
MCPIP-1 is classified as a negative regulator and an antiinflammatory molecule; its primary role was dedicated mainly to the inhibition of NFκB-dependent expression of proinflammatory cytokines
We revealed that the antiinflammatory role of MCPIP-1 is much more comprehensive than previously suggested as it controls the accumulation of neutrophils in an inflammatory milieu

Summary

Introduction

Monocyte chemoattractant protein-induced protein-1 (MCPIP-1), called Regnase-1, is a potent negative regulator of the inflammatory response. MCPIP-1 is a multidomain protein, composed of ubiquitin-binding and RNase-like PIN domains. Both domains are crucial determinants of the anti-inflammatory function of MCPIP-1. Its involvement in deubiquitination process provides inhibition of LPS- and IL-1-induced NF-κB signaling pathway, whereas RNase activity controls mRNA level for proinflammatory molecules, like IL-6, IL-1β, or IL-8 [1,2,3,4,5]. MCPIP-1 seems to play a role in processes of cell differentiation, osteoclastogenesis, angiogenesis, adipogenesis, and cell death [6,7,8,9]. MCPIP-1-deficient mice display restrained apoptosis and enhanced proliferation of epithelial

Methods

Results

Conclusion