Diminished neutrophil extracellular trap (NET) formation is a novel innate immune deficiency induced by acute ethanol exposure in polymicrobial sepsis, which can be rescued by CXCL1

Authors

Liliang Jin, Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, United States of America.
Sanjay Batra, Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, United States of America.
Samithamby Jeyaseelan, Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, United States of America.

Document Type

Article

Publication Date

9-1-2017

Abstract

Polymicrobial sepsis is the result of an exaggerated host immune response to bacterial pathogens. Animal models and human studies demonstrate that alcohol intoxication is a key risk factor for sepsis-induced mortality. Multiple chemokines, such as CXCL1, CXCL2 and CXCL5 are critical for neutrophil recruitment and proper function of neutrophils. However, it is not quite clear the mechanisms by which acute alcohol suppresses immune responses and whether alcohol-induced immunosuppression can be rescued by chemokines. Thus, we assessed whether acute ethanol challenge via gavage diminishes antibacterial host defense in a sepsis model using cecal ligation and puncture (CLP) and whether this immunosuppression can be rescued by exogenous CXCL1. We found acute alcohol intoxication augments mortality and enhances bacterial growth in mice following CLP. Ethanol exposure impairs critical antibacterial functions of mouse and human neutrophils including reactive oxygen species production, neutrophil extracellular trap (NET) formation, and NET-mediated killing in response to both Gram-negative (E. coli) and Gram-positive (Staphylococcus aureus) pathogens. As compared with WT (C57Bl/6) mice, CXCL1 knockout mice display early mortality following acute alcohol exposure followed by CLP. Recombinant CXCL1 (rCXCL1) in acute alcohol challenged CLP mice increases survival, enhances bacterial clearance, improves neutrophil recruitment, and enhances NET formation (NETosis). Recombinant CXCL1 (rCXCL1) administration also augments bacterial killing by alcohol-treated and E. coli- and S. aureus-infected neutrophils. Taken together, our data unveils novel mechanisms underlying acute alcohol-induced dysregulation of the immune responses in polymicrobial sepsis, and CXCL1 is a critical mediator to rescue alcohol-induced immune dysregulation in polymicrobial sepsis.

Publication Source (Journal or Book title)

PLoS pathogens

First Page

e1006637

Recommended Citation

Jin, L., Batra, S., & Jeyaseelan, S. (2017). Diminished neutrophil extracellular trap (NET) formation is a novel innate immune deficiency induced by acute ethanol exposure in polymicrobial sepsis, which can be rescued by CXCL1. PLoS pathogens, 13 (9), e1006637. https://doi.org/10.1371/journal.ppat.1006637