CXCL1 contributes to host defense in polymicrobial sepsis via modulating T cell and neutrophil functions

L Jin, S Batra, DN Douda, N Palaniyar… - The Journal of …, 2014 - journals.aai.org
The Journal of immunology, 2014journals.aai.org
Severe bacterial sepsis leads to a proinflammatory condition that can manifest as septic
shock, multiple organ failure, and death. Neutrophils are critical for the rapid elimination of
bacteria; however, the role of neutrophil chemoattractant CXCL1 in bacterial clearance
during sepsis remains elusive. To test the hypothesis that CXCL1 is critical to host defense
during sepsis, we used CXCL1-deficient mice and bone marrow chimeras to demonstrate
the importance of this molecule in sepsis. We demonstrate that CXCL1 plays a pivotal role in …
Abstract
Severe bacterial sepsis leads to a proinflammatory condition that can manifest as septic shock, multiple organ failure, and death. Neutrophils are critical for the rapid elimination of bacteria; however, the role of neutrophil chemoattractant CXCL1 in bacterial clearance during sepsis remains elusive. To test the hypothesis that CXCL1 is critical to host defense during sepsis, we used CXCL1-deficient mice and bone marrow chimeras to demonstrate the importance of this molecule in sepsis. We demonstrate that CXCL1 plays a pivotal role in mediating host defense to polymicrobial sepsis after cecal ligation and puncture in gene-deficient mice. CXCL1 appears to be essential for restricting bacterial outgrowth and death in mice. CXCL1 derived from both hematopoietic and resident cells contributed to bacterial clearance. Moreover, CXCL1 is essential for neutrophil migration, expression of proinflammatory mediators, activation of NF-κB and MAPKs, and upregulation of adhesion molecule ICAM-1. rIL-17 rescued impaired host defenses in cxcl1−/− mice. CXCL1 is important for IL-17A production via Th17 differentiation. CXCL1 is essential for NADPH oxidase–mediated reactive oxygen species production and neutrophil extracellular trap formation. This study reveals a novel role for CXCL1 in neutrophil recruitment via modulating T cell function and neutrophil-related bactericidal functions. These studies suggest that modulation of CXCL1 levels in tissues and blood could reduce bacterial burden in sepsis.
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