journal contribution
posted on 2024-04-02, 07:23 authored by Silvia Carnevale, Andrea Ponzetta, Anna Rigatelli, Roberta Carriero, Simone Puccio, Domenico Supino, Giovanna Grieco, Piera Molisso, Irene Di Ceglie, Francesco Scavello, Chiara Perucchini, Fabio Pasqualini, Camilla Recordati, Claudio Tripodo, Beatrice Belmonte, Andrea Mariancini, Paolo Kunderfranco, Giuseppe Sciumè, Enrico Lugli, Eduardo Bonavita, Elena Magrini, Cecilia Garlanda, Alberto Mantovani, Sebastien Jaillon Figure S6. Neutrophil infiltration is associated with tissue repair gene signatures in patients with ulcerative colitis.
Related to Figure 6.
A-E) Enrichment plots for gene ontology term epithelial cell (GO:Epithelial Cell Proliferation (A, D); GO:Epithelial Cell Development (B, E); GO:Maintanance of Gastrointestinal Epithilium (C)) in CSF3Rhigh versus CSF3Rlow UC patients GSE109142 (A-C) GSE87473 (D-E). F-K) Enrichment plots for gene ontology term antimicrobial response (GO:Response to molecule of bacterial origin (F, I); GO:Defense response to bacterium; GO:Antimicrobial humoral immune response mediated by antimicrobial peptides) in CSF3Rhigh versus CSF3Rlow UC patients GSE109142 (F-H) and GSE87473 (I-K). CSF3R gene expression values were stratified by quartiles and patients belonging to the upper (GSE109142 n=51; GSE87473 n=21) and lower GSE109142 n=51; GSE97473 n=21) quartiles were considered for differential expression analysis. FDR, false discovery rate.
Funding
Ministero della Salute (Italy Ministry of Health)
Fondazione AIRC per la ricerca sul cancro ETS (AIRC)
Ministero dell'Università e della Ricerca (MUR)
History
ARTICLE ABSTRACT
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 (Csf3r−/− 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. Csf3r−/− mice showed increased susceptibility to colitis and colitis-associated colorectal cancer compared with 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 IL22 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 IL22-dependent tissue repair pathway.
