Faculty, Staff and Student Publications
Language
English
Publication Date
12-15-2024
DOI
10.4049/jimmunol.2400129
PMID
39485006
PMCID
PMC11611642
PubMedCentral® Posted Date
12-15-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Aberrant intestinal inflammation plays a critical role in the development of colitis-associated colorectal cancer (CAC), yet the mechanisms controlling tumor development by the myeloid immune compartment are not fully understood. Although altered microRNA expression is observed in CAC, it is also unclear how myeloid-specific microRNAs impact the inflammatory process that underpins the continuum from ulcerative colitis to tumorigenesis. In this study, we report that miR-223 acts to limit myeloid-driven inflammation in the azoxymethane (AOM)-dextran sodium sulfate (DSS) model of CAC in mice. In this model, miR-223-/y mice present with significantly larger tumors with an enhanced proliferative signature. Immunoprofiling showed that miR-223-/y mice have significantly increased colonic myeloid immune infiltrate (neutrophils, monocytes, and macrophages) following AOM-DSS. This was accompanied by an increased inflammatory chemokine and cytokine signature for monocytes and neutrophils. Bone marrow chimera studies demonstrate that myeloid-expressed miR-223 is responsible for the enhanced tumor proliferation and inflammatory response. RNA sequencing identified several pathways that could be contributing to the development of CAC in miR-223-/y mice, including the IL-6/IL-17a cytokine family and STAT3 signaling. Lastly, neutrophil depletion with an anti-GR1 Ab (Ly6G/Ly6C) during the initial phase of the AOM-DSS model reduced the tumor burden in miR-223-/y mice. Collectively, our data indicate that miR-223 is an important regulator of mucosal inflammation and acts to constrain the progression from ulcerative colitis to CAC by limiting myeloid-associated inflammation.
Keywords
Animals, MicroRNAs, Mice, Myeloid Cells, Chemokines, Carcinogenesis, Mice, Inbred C57BL, Colitis, Dextran Sulfate, Azoxymethane, Disease Models, Animal, Colitis-Associated Neoplasms, Mice, Knockout
Published Open-Access
yes
Recommended Citation
Flynn, Ciara L; Markey, Gary E; Neudecker, Viola; et al., "The MicroRNA miR-223 Constrains Colitis-associated Tumorigenesis by Limiting Myeloid Cell Infiltration and Chemokine Expression" (2024). Faculty, Staff and Student Publications. 793.
https://digitalcommons.library.tmc.edu/uthmed_docs/793