TLR22-Induced Pro-Apoptotic mtROS Abets UPR-Mediated Mitochondrial Fission in -Infected Headkidney Macrophages of .

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.