Abstract
Sepsis is the leading cause of death in intensive care units in the US, and it is known that chronic alcohol use is associated with higher incidence of sepsis, longer ICU stays, and higher mortality from sepsis. Both sepsis and chronic alcohol use are associated with immune deficits such as decreased lymphocyte numbers, impaired innate immunity, delayed-type hypersensitivity reactions, and susceptibility to infections; however, understanding of specific pathways of interaction or synergy between these two states of immune dysregulation is lacking. This study therefore sought to elucidate mechanisms underlying the immune dysregulation observed during sepsis in the setting of chronic alcohol exposure. Using a murine model of chronic ethanol ingestion followed by sepsis induction via cecal ligation and puncture, we determined that while CD4+ and CD8+ T cells isolated from alcohol fed mice eventually expressed the same cellular activation markers (CD44, CD69, and CD43) and effector molecules (IFN-γ, TNF) as their water fed counterparts, there was an overall delay in the acquisition of these phenotypes. This early lag in T cell activation was associated with significantly reduced IL-2 production at a later timepoint in both the CD4+ and CD8+ T cell compartments in alcohol sepsis, as well as with a reduced accumulation of CD8dim activated effectors. Taken together, these data suggest that delayed T cell activation may result in qualitative differences in the immune response to sepsis in the setting of chronic alcohol ingestion.
Highlights
Alcohol use disorders are prevalent in the United States, with recent epidemiologic data based on the American Psychiatric Association’s clinical diagnostic criteria (DSM-5) estimating twelve month and lifetime prevalence of the condition to be 13.9% and 29.1%, respectively [1, 2]
One would expect that in the setting of a polymicrobial septic insult, the CD44hi population of T cells would be a source of rapid recall response to initiate the adaptive immune response, and the fact that we observed a relative delay in the activation kinetics of memory T cells in the setting of chronic alcohol ingestion could be a potential contributor to the observed increase in mortality observed in alcohol fed septic animals
When placed within the context of what is known about the impact of CD43- and CD69-mediated signals on cytokine production, our results further suggest that the observed delayed kinetics of expression of both CD43 and CD69 on CD4+ and CD8+ T cell in alcohol fed animals relative to water-fed animals following cecal ligation and puncture (CLP) may mechanistically underlie the significant alterations in cytokines observed in these animals
Summary
Alcohol use disorders are prevalent in the United States, with recent epidemiologic data based on the American Psychiatric Association’s clinical diagnostic criteria (DSM-5) estimating twelve month and lifetime prevalence of the condition to be 13.9% and 29.1%, respectively [1, 2]. Previous murine studies throughout the 1990s demonstrated the Th2 skewing resulting from chronic ethanol administration was associated with decreased T cell production of IFN-γ, increased IL-4, and down-regulation of IL-12, with preservation of T cell proliferation and IL-2 production. These deficits were subsequently localized to the APC and shown to be rescued by administration of IL-12 [6]. In a murine model of Influenza A virus (IAV) infection following ethanol ingestion, ethanol was associated with increased mortality, increased viral titers, and decreased IAV-specific CD8 T cells with reduced proliferation, IFN-γ production and degranulation induced target cell lysis[12]
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