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Supplementary Figure S4 from Neutrophils Mediate Protection Against Colitis and Carcinogenesis by Controlling Bacterial Invasion and IL22 Production by γδ T Cells

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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 S4. Neutrophil deficiency is associated with decreased expression of IL-22 by γδ T cells. Related to Figure 4-5. A-C) Representative gating strategy used to gate myeloid population (A), lymphoid population (B) and innate lymphoid cells (ILC) (C) in colon LP. UTC: unconventional T cells (TCRβ+, CD8-, CD4-). D) IL-22 expression in myeloid cells derived from DSS-treated Csf3r+/+(n=3), Csf3r-/-(n=3) stimulated 4 hours with IL-23 analyzed by FACS. E-F) Expression of IL-22 by lymphoid cells derived from DSS-treated Csf3r+/+(n=4), Csf3r-/- (n=4) stimulated 4 hours with IL-23 plus IL-1β (E) and PMA plus ionomycin (F) analyzed by FACS. A-F) Representative data of three independent experiments. D-F) Multiple t-test. Data are mean ± SEM. *** p < 0.001 ** p < 0.01 * p < 0.05.

Funding

Ministero della Salute (Italy Ministry of Health)

Fondazione AIRC per la ricerca sul cancro ETS (AIRC)

Ministero dell'Università e della Ricerca (MUR)

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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.

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