MCPIP-1-Mediated Immunosuppression of Neutrophils Exacerbates Acute Bacterial Peritonitis and Liver Injury

Abstract

Monocyte chemotactic protein-1-induced protein-1 (MCPIP-1) is highly expressed in activated immune cells and negatively regulates immune responses, while the mechanisms underlying the immunoregulation of neutrophils in acute bacterial infection and liver injury remain elusive. Here, we examined the role of MCPIP-1 in regulating neutrophil functions during acute bacterial peritonitis and liver injury. Mice with myeloid cell-specific overexpression (<i>Mcpip</i>^Mye-tg) or knockout (<i>Mcpip</i>^ΔMye) of MCPIP-1 were generated. We found that reactive oxygen species and myeloperoxidase production, formation of neutrophil extracellular traps, and migratory capacity were deficient in <i>Mcpip</i>^Mye-tg neutrophils but enhanced in <i>Mcpip</i>^ΔMye neutrophils. The recruitment of neutrophils and pathogen clearance were markedly suppressed in <i>Mcpip</i>^Mye-tg mice following intraperitoneal infection with <i>Salmonella typhimurium</i> while intensified in <i>Mcpip</i>^ΔMye mice. Severe acute <i>S. typhimurium</i>-infected peritonitis and liver injury occurred in <i>Mcpip</i>^Mye-tg mice but were alleviated in <i>Mcpip</i>^ΔMye mice. RNA sequencing, RNA-binding protein immunoprecipitation and qPCR analysis revealed that MCPIP-1 downregulated the protective functions of neutrophils via degrading the mRNA of cold inducible RNA-binding protein. Consistently, MCPIP-1 was highly expressed in neutrophils of patients with acute infectious diseases, especially in those with liver injury. Collectively, we uncover that MCPIP-1 negatively regulates the antibacterial capacities of neutrophils, leading to exacerbating severe acute bacterial peritonitis and liver injury. It may serve as a candidate target for maintaining neutrophil homeostasis to control acute infectious diseases.