Deletion of MCP-1 enhances susceptibility to carbapenem-resistant Klebsiella pneumoniae via modulating neutrophil and macrophage function

Abstract Monocyte chemoattractant protein-1 (MCP-1) is important for monocyte recruitment to the lungs in response to bacterial infection. MCP-1 is also essential for neutrophil-dependent host defense during Escherichia coli infection. Carbapenem-Resistant Klebsiella pneumoniae (CRKP) infection has been rapidly growing as a life-threatening nosocomial disease in the U.S. and world. However, the role of chemokines and cellular responses in protective immunity to pulmonary infection with CRKP is largely unknown. Here, we investigated the role of MCP-1 in pulmonary host defense against CRKP infection using MCP-1 knockout (KO) mice. We determined survival, bacterial burden, and neutrophil influx, cytokine/chemokine expression as well as cellular functions, such as formation of neutrophil extracellular traps (NETs) and macrophage extracellular traps (METs). MCP-1 is essential for survival and restricting bacterial outgrowth organs. Compared to the C57Bl/6 (control) mice, KO mice showed impaired influx of neutrophils in the airways as assessed by nuclear cell morphology in BALF and by myeloperoxidase activity (MPO) in lung parenchyma. Moreover, the NETs and METs induced by CRKP were reduced in KO mice in both in vitro or in vivo. Intriguingly, subsequent to CRKP infection, KO mice demonstrated increased pyroptosis through enhanced activation of caspase-1, higher expression of IL-1β and cleaved gasdermin-D in the lungs. These findings enhance our understanding of the critical role of MCP-1 in modulating neutrophil function, such as NETosis, METosis and pyroptosis and suggest that therapies targeting modulation of NETs, METs and pyroptosis during CRKP infection can be explored through clinical trials.