Interferon regulatory factor 1 regulates PANoptosis to prevent colorectal cancer
Rajendra Karki, Bhesh Raj Sharma, Ein Lee, Balaji Banoth, R.K. Subbarao Malireddi, Parimal Samir, Shraddha Tuladhar, Harisankeerth Mummareddy, Amanda R. Burton, Peter Vogel, Thirumala-Devi Kanneganti
Rajendra Karki, Bhesh Raj Sharma, Ein Lee, Balaji Banoth, R.K. Subbarao Malireddi, Parimal Samir, Shraddha Tuladhar, Harisankeerth Mummareddy, Amanda R. Burton, Peter Vogel, Thirumala-Devi Kanneganti
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Research Article Immunology Oncology

Interferon regulatory factor 1 regulates PANoptosis to prevent colorectal cancer

Abstract

Interferon regulatory factor 1 (IRF1) regulates diverse biological functions, including modulation of cellular responses involved in tumorigenesis. Genetic mutations and altered IRF1 function are associated with several cancers. Although the function of IRF1 in the immunobiology of cancer is emerging, IRF1-specific mechanisms regulating tumorigenesis and tissue homeostasis in vivo are not clear. Here, we found that mice lacking IRF1 were hypersusceptible to colorectal tumorigenesis. IRF1 functions in both the myeloid and epithelial compartments to confer protection against AOM/DSS-induced colorectal tumorigenesis. We further found that IRF1 also prevents tumorigenesis in a spontaneous mouse model of colorectal cancer. The attenuated cell death in the colons of Irf1–/– mice was due to defective pyroptosis, apoptosis, and necroptosis (PANoptosis). IRF1 does not regulate inflammation and the inflammasome in the colon. Overall, our study identified IRF1 as an upstream regulator of PANoptosis to induce cell death during colitis-associated tumorigenesis.

Authors

Rajendra Karki, Bhesh Raj Sharma, Ein Lee, Balaji Banoth, R.K. Subbarao Malireddi, Parimal Samir, Shraddha Tuladhar, Harisankeerth Mummareddy, Amanda R. Burton, Peter Vogel, Thirumala-Devi Kanneganti

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Figure 4

IRF1 does not regulate inflammation in the colon.

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IRF1 does not regulate inflammation in the colon. (A) Body weight change...
(A) Body weight change of WT (n = 10) and Irf1–/– (n = 10) mice from 1 experiment (representative of 3 independent experiments). (B and C) Representative images of colon (B) and length of colon (C) in WT (n = 10) and Irf1–/– (n = 10) mice 14 days after azoxymethane (AOM) injection. (D) Histological scores. (E) Representative H&E staining of colon. Scale bar: 500 μM. (F) Immunoblot analysis of IRF1, phosphorylated and total ERK1 and ERK2 (P-ERK1/2 and ERK1/2, respectively), phosphorylated and total IκBα (P-IκBα and IκBα, respectively), phosphorylated and total STAT3 (P-STAT3 and STAT3, respectively), and GAPDH (loading control) in colons of WT and Irf1–/– mice. Blots represent data from the same biological samples run in parallel. (G) Levels of inflammatory cytokines in the colons of WT and Irf1–/– mice at day 0, 14, and 80 after AOM injection. Each symbol represents 1 individual mouse (C, D, and G). *P < 0.05; **P < 0.01; ****P < 0.0001. The 2-tailed t test (C and D) or 1-way ANOVA (G) were used. Data are from 1 experiment (representative of 3 independent experiments) (A–F) or pooled from 2 independent experiments (G). Data are represented as mean ± SEM.