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IL-1? is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity.

ABSTRACT: Environmental signals can be translated into chromatin changes, which alter gene expression. Here we report a novel concept that cells can signal chromatin damage from the nucleus back to the surrounding tissue through the cytokine interleukin-1alpha (IL-1?). Thus, in addition to its role as a danger signal, which occurs when the cytokine is passively released by cell necrosis, IL-1? could directly sense DNA damage and act as signal for genotoxic stress without loss of cell integrity. Here we demonstrate localization of the cytokine to DNA-damage sites and its subsequent secretion. Interestingly, its nucleo-cytosolic shuttling after DNA damage sensing is regulated by histone deacetylases (HDAC) and IL-1? acetylation. To demonstrate the physiological significance of this newly discovered mechanism, we used IL-1? knockout mice and show that IL-1? signaling after UV skin irradiation and DNA damage is important for triggering a sterile inflammatory cascade in vivo that contributes to efficient tissue repair and wound healing.

SUBMITTER: Cohen I

PROVIDER: S-EPMC4593953 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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IL-1α is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity.

Cohen Idan I Rider Peleg P Vornov Elena E Tomas Martin M Tudor Cicerone C Wegner Mareike M Brondani Lydia L Freudenberg Marina M Mittler Gerhard G Ferrando-May Elisa E Dinarello Charles A CA Apte Ron N RN Schneider Robert R

Scientific reports 20151006

Environmental signals can be translated into chromatin changes, which alter gene expression. Here we report a novel concept that cells can signal chromatin damage from the nucleus back to the surrounding tissue through the cytokine interleukin-1alpha (IL-1α). Thus, in addition to its role as a danger signal, which occurs when the cytokine is passively released by cell necrosis, IL-1α could directly sense DNA damage and act as signal for genotoxic stress without loss of cell integrity. Here we de ...[more]

PMID: 26439902

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Project description:It is well known that psychological stress could affect the immune system and then regulate the disease process. Previous studies mostly focused on the effects of chronic stress on diseases and immune cells. How acute stress affects the immune system remains poorly understood. In this study, after 6 hours of restraint stress or no stress, RNA was extracted from mouse peripheral blood followed by sequencing. Through bioinformatics analysis, we found that when compared with the control group, differentially expressed genes in the stress group mainly displayed up-regulated expression. Gene set enrichment analysis results showed that the enriched gene terms were mainly related to inflammatory response, defense response, wounding response, wound healing, complement activation and pro-inflammatory cytokine production. In terms of cell activation, differentiation and chemotaxis, the enriched gene terms were related to a variety of immune cells, among which neutrophils seemed more active in stress response. The results of gene set variation analysis showed that under acute stress, the inflammatory reaction dominated by innate immunity was forming. Additionally, the concentration of serum IL-1β and IL-6 increased significantly after acute stress, indicating that the body was in an inflammatory state. Importantly, we found that acute stress led to a significant increase in the number of neutrophils in peripheral blood, while the number of T cells and B cells decreased significantly through flow cytometric analysis. Through protein-protein interaction network analysis, we screened 10 hub genes, which mainly related to inflammation and neutrophils. We also found acute stress led to an up-regulation of Ccr1, Ccr2, Xcr1 and Cxcr2 genes, which were involved in cell migration and chemotaxis. Our data suggested that immune cells were ready to infiltrate into tissues in emergency through blood vessels under acute stress. This hypothesis was supported in LPS-induced acute inflammatory models. After 48 hours of LPS treatment, flow cytometric analysis showed that the lungs of mice with acute stress were characterized by increased neutrophil infiltration, decreased T cell and B cell infiltration. Immunohistochemical analysis also showed that acute stress led to more severe lung inflammation. If mice received repeat acute stress and LPS stimulation, the survival rate was significantly lower than that of mice only stimulated by LPS. Altogether, acute stress led to rapid mobilization of the immune system, and the body presented an inflammatory state dominated by innate immune response represented by neutrophils.

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IL-1? is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity.

Publications

IL-1α is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity.

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