Neutrophils mediate protection against colitis and carcinogenesis by controlling bacterial invasion and IL-22 production by gamma delta T cells
Menée notamment à l'aide de modèles murins, de séries de données portant sur des patients ainsi que d'analyses histologiques et immunohistochimiques d'échantillons coliques, cette étude met en évidence un mécanisme par lequel les neutrophiles induisent une protection contre l'inflammation intestinale et la carcinogenèse en contrôlant l'invasion bactérienne et la production d'interleukines IL-22 par les lymphocytes T gamma delta
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 pathological contexts by using a rigorous genetic approach. Neutrophil-deficient mice (Csf3r-/- mice) were used in classic models of colitis and colitis-associated colorectal cancer and the role of neutrophils was assessed by histological, cellular and molecular analyses coupled with adoptive cell transfer. We also performed correlative analyses using human datasets. Csf3r-/- mice showed increased susceptibility to colitis and colitis-associated colorectal cancer compared to control Csf3r+/+ mice and adoptive transfer of neutrophils in Csf3r-/- mice reverted the phenotype. In colitis, Csf3r-/- 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 IL-22 production. In patients with ulcerative colitis, expression of CSF3R was positively correlated with IL22 and IL23 expression. Moreover, gene signatures associated with epithelial-cell development, proliferation, and antimicrobial response were enriched in CSF3Rhigh 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 IL-22-dependent tissue repair pathway.