Data from Neutrophils Mediate Protection Against Colitis and Carcinogenesis by Controlling Bacterial Invasion and IL22 Production by γδ T Cells

Abstract

<div>Abstract<p>Neutrophils are the most abundant leukocytes in human blood and play a primary role in resistance against invading microorganisms and in the acute inflammatory response. However, their role in colitis and colitis-associated colorectal cancer is still under debate. This study aims to dissect the role of neutrophils in these pathologic contexts by using a rigorous genetic approach. Neutrophil-deficient mice (<i>Csf3r<sup>−/−</sup></i> mice) were used in classic models of colitis and colitis-associated colorectal cancer and the role of neutrophils was assessed by histologic, cellular, and molecular analyses coupled with adoptive cell transfer. We also performed correlative analyses using human datasets. <i>Csf3r<sup>−/−</sup></i> mice showed increased susceptibility to colitis and colitis-associated colorectal cancer compared with control <i>Csf3r<sup>+/+</sup></i> mice and adoptive transfer of neutrophils in <i>Csf3r<sup>−/−</sup></i> mice reverted the phenotype. In colitis, <i>Csf3r<sup>−/−</sup></i> mice showed increased bacterial invasion and a reduced number of healing ulcers in the colon, indicating a compromised regenerative capacity of epithelial cells. Neutrophils were essential for γδ T-cell polarization and IL22 production. In patients with ulcerative colitis, expression of <i>CSF3R</i> was positively correlated with <i>IL22</i> and <i>IL23</i> expression. Moreover, gene signatures associated with epithelial-cell development, proliferation, and antimicrobial response were enriched in <i>CSF3R<sup>high</sup></i> patients. Our data support a model where neutrophils mediate protection against intestinal inflammation and colitis-associated colorectal cancer by controlling the intestinal microbiota and driving the activation of an IL22-dependent tissue repair pathway.</p></div>