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 Ca2+ 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.

中文翻译：

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CpG-ODN 介导的 TLR9 先天免疫信号和钙稳态失调集中在 NFκB 抑制蛋白 IκBβ 上以驱动 IL1α 和 IL1β 表达。

无菌性炎症导致许多与线粒体损伤相关的病理状态。线粒体损伤会破坏钙稳态并导致释放富含 CpG 的线粒体 DNA。CpG 刺激的 TLR9 先天免疫信号和无菌性炎症的作用已得到充分研究；然而，钙稳态失调如何影响这种信号传导尚不清楚。因此，我们研究了小鼠巨噬细胞中细胞内钙和 CpG 诱导的 TLR9 信号之间的关系。我们发现 CpG-ODN 诱导的 NFκB 依赖性 IL1α 和 IL1β 表达被钙螯合和神经钙蛋白抑制显着减弱，这一发现是由抑制 NFκB 抑制蛋白 IκBβ 的降解介导的。相反，钙离子载体暴露增加了 CpG 诱导的 IκBβ 降解和 IL1α 和 IL1β 表达。这些结果表明，通过其对 IκBβ 降解的影响，增加的细胞内 Ca2+ 驱动促炎性 TLR9 介导的先天免疫反应。这些结果对研究线粒体应激和损伤下游的先天免疫信号具有重要意义。