CXCL1 Contributes to Host Defense in Polymicrobial Sepsis via Modulating T Cell and Neutrophil Functions

Abstract

Severe bacterial sepsis leads to a pro-inflammatory 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 following cecal ligation and puncture (CLP) 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 pro-inflammatory mediators, activation of Nuclear-Factor-κ-B (NF-κB) and Mitogen-Activated Protein (MAP) kinases and upregulation of adhesion molecule Intercellular Adhesion Molecule-1 (ICAM-1). Recombinant interleukin 17 (IL-17) rescued impaired host defenses in cxcl1−/− mice. CXCL1 is important for IL-17A production via Th17 differentiation. CXCL1 is essential for Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase-mediated reactive oxygen species production and neutrophil extracellular trap (NET) 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.

Clinical Association of Chemokine (C-X-C motif) Ligand 1 (CXCL1) with Interstitial Pneumonia with Autoimmune Features (IPAF)

“…6C and D), which may indicate the ability of CXCL1 to promote neutrophil chemotaxis within the alveolar compartment in both IPAF and IIP. Our findings in subjects with IPAF and IIP parallel analogous observations in patients with other disease conditions in which the accumulation of neutrophils was shown to be driven by CXCL134519.…”

Regulation of tissue infiltration by neutrophils

“…Interestingly, CXCL1 and CXCL2 are pre-formed in granules of mast cells, and their rapid TLR-4-dependent release upon inflammatory stimulation allows for rapid neutrophil recruitment [19]. Furthermore, CXCL1 is central for neutrophil migration and contributes to bactericidal functions of neutrophils during polymicrobial sepsis [20]. …”

Gram-Negative Pneumonia Alters Large-Vein Cell-Adhesion Molecule Profile and Potentiates Experimental Stasis Venous Thrombosis

“…Currently, a dual E-sel and P-sel inhibitor is in clinical trials for the treatment of human deep-vein thrombosis (DVT) (NCT02271113). Besides VT, these CAMs have been found to be elevated in humans with endotoxemia [39] and in murine models of infections such as cecal ligation and puncture [40–42]. Similarly, inhibition of leukocyte interactions via disruption of CAM interactions has been shown to decrease cytokine storm and lethality in a mouse model of cecal ligation and puncture [43].…”