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. Author manuscript; available in PMC: 2018 May 31.
Published in final edited form as: Toxicol Appl Pharmacol. 2016 Jul 25;308:46–58. doi: 10.1016/j.taap.2016.07.015

Fig. 7.

Fig. 7

Flow diagram depicting the mechanism by which ATO treatment blocks macrophage functions and induces apoptosis in ATF4-dependent manner. ATO activates ATF4, a UPR signaling transcription factor, in murine macrophages, which dysregulates multiple macrophage functions including cytokines release, bacterial engulfment and clearance of engulfed bacteria. In ATO-treated macrophages, sustained activation of ATF4 leads to apoptosis via multiple pathways. Ca++-dependent calpain-1/caspase-12-mediated apoptosis and mitochondrial-dependent apoptosis via release of cytochrome-c from mitochondria to cytoplasm have been recorded. Overall, these effects may lead to dampening of macrophage-dependent innate immune responses. The role of ATF4 in ATO-mediated macrophage dysregulation was ascertained by the genetic approaches where knocking down of ATF4 afforded significantly protection against ATO-mediated impairment of macrophage functions. Role of calcium homeostasis in this toxicity could be confirmed by the treatment of these macrophages with Ca++ channel blocker or Ca++ chelators which attenuated ATO-induced calpain-1/caspase-12-mediated apoptosis and perhaps other functions related to ATF4 activation.