UC Irvine

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a food-borne pathogen that causes severe diarrhea but can also cause fatal bacteremia if it reaches the bloodstream. During S. Typhimurium infection, a massive number of neutrophils migrate to the intestine; this response is important to prevent dissemination of S. Typhimurium into the bloodstream. Although some of the mechanisms by which neutrophils are protective during S. Typhimurium infection are known, the specific signals regulating their recruitment to the intestinal mucosa are not well elucidated. Most neutrophils express the chemokine receptor CXCR2, through which neutrophils sense CXC chemokines from inflamed or infected tissues. To better understand the role of CXCR2 during S. Typhimurium infection, we depleted CXCR2+ neutrophils in mice using antibody treatment, and we employed mice with a deletion of the Cxcr2 gene. During S. Typhimurium infection, mice lacking CXCR2+ neutrophils showed significantly fewer neutrophils in intestinal tissue, indicating that CXCR2 is a major receptor for intestinal neutrophil recruitment during S. Typhimurium colitis. Consistent with a protective role for neutrophils, S. Typhimurium numbers in peripheral organs were higher in mice lacking CXCR2+ neutrophils. Notably, and reported here for the first time, Cxcr2-/- mice exhibit fewer B cells in Peyer’s patches, which correlated to a nearly 100-fold higher S. Typhimurium burden in this tissue. Furthermore, we demonstrated that Peyer’s patch B cells migrate in response to CXCR2 chemokines, and that the role of Peyer’s patch B cells in protection against S. Typhimurium is independent of intestinal IgA levels. To better understand the specific contribution of neutrophil recruitment in protection against Salmonella, we generated mice selectively lacking Cxcr2 in granulocytes, which exhibited similar defects in neutrophil migration and S. Typhimurium dissemination as Cxcr2-/- mice. In contrast to Cxcr2-/- mice, granulocyte-specific deletion of Cxcr2 was not associated with higher S. Typhimurium colonization in Peyer’s patches, and Peyer’s patch B cells were not reduced. Altogether, this work expanded our understanding of CXCR2-mediated neutrophil recruitment in influencing outcomes of Salmonella infection and uncovered an important, IgA-independent role for CXCR2 on B cells in Peyer’s patches and in host defense against Salmonella intestinal infection.