Microbial exposure increases the magnitude and diversity of peritoneal inflammatory cell infiltrates and cytokine storm during sepsis

Abstract

Abstract Sepsis – defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection - remains a major healthcare burden and cause of death in the United States and worldwide. While there has been a vast expansion in knowledge regarding the impact of sepsis on the immune system, virtually all preclinical sepsis research to date has relied on using mice housed under specific pathogen-free (SPF) conditions. Environmental pathogen exposure is one important difference between basic human and laboratory mouse biology that must be considered when using mice to evaluate immune system fitness. Interestingly, B6 mice that have been cohoused with pet store mice (to permit microbial transfer and immune system maturation; “CoH” mice) exhibit exaggerated acute hyperinflammation, morbidity, and mortality during cecal ligation and puncture (CLP)-induced polymicrobial sepsis compared to SPF B6 mice. To understand the mechanism of this increased acute response, we examined peritoneal immune cell composition in SPF and CoH mice before and after sepsis induction. CoH mice have more ‘large’ MHC IIloF4/80hi and ‘small’ MHC IIhiF4/80lo peritoneal macrophages (LPM and SPM) and neutrophils than SPF mice at baseline. Upon the induction of polymicrobial-induced peritonitis, there was increased recruitment of neutrophils, monocytes, T cells, and NK cells into the peritoneum of CoH mice vs. SPF mice. This increased immune cell influx correlated with increased CXCL1 and CCL2 in peritoneal lavage samples from CoH mice. CoH mice devoid of neutrophils or LPM exhibit reduced cytokine storm and improved outcomes after sepsis induction. These data suggest the cells of the innate immune system govern the magnitude of the acute septic response.