CpG-ODN-mediated TLR9 Innate Immune Signalling and Calcium Dyshomeostasis Converge on the NFκB Inhibitory Protein IκBβ to Drive IL1α and IL1β Expression

Overview

Journal Immunology

Specialty Allergy & Immunology

Date 2020 Feb 18

PMID 32064589

Citations 5

Authors

Robyn De Dios

Leanna Nguyen

Sankar Ghosh

Sarah McKenna

Clyde J Wright

Affiliations

Soon will be listed here.

Abstract

Sterile inflammation contributes to many pathological states associated with mitochondrial injury. Mitochondrial injury disrupts calcium homeostasis and results in the release of CpG-rich mitochondrial DNA. The role of CpG-stimulated TLR9 innate immune signalling and sterile inflammation is well studied; however, how calcium dyshomeostasis affects this signalling is unknown. Therefore, we interrogated the relationship beτween intracellular calcium and CpG-induced TLR9 signalling in murine macrophages. We found that CpG-ODN-induced NFκB-dependent IL1α and IL1β expression was significantly attenuated by both calcium chelation and calcineurin inhibition, a finding mediated by inhibition of degradation of the NFκB inhibitory protein IκBβ. In contrast, calcium ionophore exposure increased CpG-induced IκBβ degradation and IL1α and IL1β expression. These results demonstrate that through its effect on IκBβ degradation, increased intracellular Ca drives a pro-inflammatory TLR9-mediated innate immune response. These results have implications for the study of innate immune signalling downstream of mitochondrial stress and injury.

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