Immunobiology Laboratory, Department of Zoology, University of Delhi, Delhi, India.
Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, Delhi, India.
Front Immunol. 2022 Jul 4;13:931021. doi: 10.3389/fimmu.2022.931021. eCollection 2022.
Toll-like receptors (TLRs) are epitomized as the first line of defense against pathogens. Amongst TLRs, TLR22 is expressed in non-mammalian aquatic vertebrates, including fish. Using headkidney macrophages (HKM) of , we reported the pro-apoptotic and microbicidal role of TLR22 in infection. Mitochondria act as a central scaffold in the innate immune system. However, the precise molecular mechanisms underlying TLR22 signaling and mitochondrial involvement in -pathogenesis remain unexplored in fish. The aim of the present study was to investigate the nexus between TLR22 and mitochondria in pro-apoptotic immune signaling circuitry in -infected HKM. We report that TLR22-induced mitochondrial-Ca [Ca] surge is imperative for mtROS production in -infected HKM. Mitigating mtROS production enhanced intracellular bacterial replication implicating its anti-microbial role in -pathogenesis. Enhanced mtROS triggers expression leading to prolonged expression. CHOP prompts mitochondrial unfolded protein response (UPR) leading to the enhanced expression of mitochondrial fission marker , implicating mitochondrial fission in pathogenesis. Inhibition of mitochondrial fission reduced HKM apoptosis and increased the bacterial burden. Additionally, TLR22-mediated alterations in mitochondrial architecture impair mitochondrial function (ΔΨ loss and cytosolic accumulation of cyt ), which in turn activates caspase-9/caspase-3 axis in -infected HKM. Based on these findings we conclude that TLR22 prompts mtROS generation, which activates the HIF-1α/CHOP signalosome triggering UPR-induced mitochondrial fragmentation culminating in caspase-9/-3-mediated HKM apoptosis and bacterial clearance.
Toll 样受体 (TLRs) 是抵御病原体的第一道防线的代表。在 TLRs 中，TLR22 在包括鱼类在内的非哺乳动物水生脊椎动物中表达。我们使用头肾巨噬细胞 (HKM) ，报道了 TLR22 在 感染中的促凋亡和杀菌作用。线粒体在先天免疫系统中充当中央支架。然而，TLR22 信号转导和线粒体在鱼类 发病机制中的参与的确切分子机制仍未得到探索。本研究的目的是研究 TLR22 和线粒体在 -感染 HKM 中促凋亡免疫信号通路中的关系。我们报告 TLR22 诱导的线粒体-Ca [Ca] 激增对于 -感染 HKM 中线粒体 ROS (mtROS) 的产生是必要的。减轻 mtROS 的产生增强了细胞内细菌复制，表明其在 发病机制中的抗菌作用。增强的 mtROS 触发 表达，导致 表达延长。CHOP 促使线粒体未折叠蛋白反应 (UPR)，导致线粒体分裂标志物 的表达增强，表明线粒体分裂在 发病机制中起作用。抑制线粒体分裂可减少 HKM 凋亡并增加细菌负荷。此外，TLR22 介导的线粒体结构改变会损害线粒体功能（ΔΨ 丧失和细胞质中 cyt 的积累），这反过来又会在 -感染的 HKM 中激活 caspase-9/caspase-3 轴。基于这些发现，我们得出结论，TLR22 促使 mtROS 的产生，激活 HIF-1α/CHOP 信号体，触发 UPR 诱导的线粒体片段化，最终导致 caspase-9/-3 介导的 HKM 凋亡和细菌清除。
