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.
Highlights
Sepsis is a complex clinical manifestation of dysregulated host inflammatory responses to infection causing damage to vital organs that often results in death [1]
Our findings indicate that acute alcohol-mediated reductions in NETosis and NETmediated extracellular killing of bacteria contribute to the impaired bacterial clearance in polymicrobial sepsis as a novel mechanism, and CXC ligand 1 (CXCL1) rescues antibacterial defense, such as neutrophil recruitment and function in alcohol-challenged cecal ligation and puncture (CLP) mice
Acute alcohol intoxicated mice are more susceptible to polymicrobial sepsis To explore the potential effect of alcohol on host survival in response to polymicrobial sepsis, C57BL/6 (Wild-type: WT) mice were subjected to CLP-induced sepsis in the presence or absence of acute alcohol administration and the survival of animals was monitored up to 10 days post-CLP
Summary
Sepsis is a complex clinical manifestation of dysregulated host inflammatory responses to infection causing damage to vital organs that often results in death [1]. Treatment of sepsis requires prolonged intensive care and results in an increased economic burden. Alcohol abuse is a leading risk factor for mortality, causing around 100,000 deaths per year [2, 3]. Ethanol consumption is associated with an increased incidence and severity of a broad spectrum of natural infections in humans and experimental animals [1, 3]. Human studies and animal models unequivocally demonstrate that acute alcohol intoxication is a leading risk factor for mortality associated with sepsis [4,5,6,7]. The molecular and cellular pathways underlying this association are unclear
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