Immune regulator IRF1 contributes to ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosome activation and inflammatory cell death (PANoptosis).

Abstract

The innate immune system provides the first line of defense against pathogens and cellular insults and is activated by pattern recognition receptors sensing pathogen- or damage-associated molecular patterns. This activation can result in inflammation via cytokine release as well as the induction of lytic regulated cell death (RCD). Innate immune signaling can also induce the expression of interferon regulatory factor 1 (IRF1), an important molecule in regulating downstream inflammation and cell death. While IRF1 has been shown to modulate some RCD pathways, a comprehensive evaluation of its role in inflammatory cell death pathways is lacking. Here, we examined the role of IRF1 in cell death during inflammasome and PANoptosome activation using live cell imaging, Western blotting, and ELISA in primary murine macrophages. IRF1 contributed to the induction of ZBP1- (Z-DNA binding protein 1), AIM2- (absent in melanoma-2), RIPK1- (receptor interacting protein kinase 1), and NLRP12 (NOD-like receptor family, pyrin domain-containing 12)-PANoptosome activation and PANoptosis. Furthermore, IRF1 regulated the cell death under conditions where inflammasomes, along with caspase-8 and RIPK3, act as integral components of PANoptosomes to drive PANoptosis. However, it was dispensable for other inflammasomes that form independent of the PANoptosome to drive pyroptosis. Overall, these findings define IRF1 as an upstream regulator of PANoptosis and suggest that modulating the activation of molecules in the IRF1 pathway could be used as a strategy to treat inflammatory and infectious diseases associated with aberrant inflammatory cell death.

• Authors: Bhesh Raj Sharma, Rajendra Karki, Yetirajam Rajesh, Thirumala-Devi Kanneganti
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 299 Issue 9 Pg. 105141 (09 2023) ISSN: 1083-351X [Electronic] United States
• PMID: 37557956 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Aim2 protein, mouse
• DNA-Binding Proteins
• Inflammasomes
• Interferon Regulatory Factor-1
• Intracellular Signaling Peptides and Proteins
• Irf1 protein, mouse
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP12 protein, mouse
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk1 protein, mouse
• RNA-Binding Proteins
• Zbp1 protein, mouse
• Casp8 protein, mouse
• Ripk3 protein, mouse

Topics

• Animals
• Mice
• Cell Death
• DNA-Binding Proteins
• Inflammasomes (metabolism)
• Inflammation
• Interferon Regulatory Factor-1 (genetics, metabolism)
• Intracellular Signaling Peptides and Proteins (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Pyroptosis
• Receptor-Interacting Protein Serine-Threonine Kinases
• RNA-Binding Proteins
• Macrophages (immunology)