title: Activating transcription factor 4 underlies the pathogenesis of arsenic trioxide-mediated impairment of macrophage innate immune functions.
abstract: Chronic arsenic exposure to humans is considered immunosuppressive with augmented susceptibility to several infectious diseases. The exact molecular mechanisms, however, remain unknown. Earlier, we showed the involvement of unfolded protein response (UPR) signaling in arsenic-mediated impairment of macrophage functions. Here, we show that activating transcription factor 4 (ATF4), a UPR transcription factor, regulates arsenic trioxide (ATO)-mediated dysregulation of macrophage functions. In ATO-treated ATF4(+/+) wild-type mice, a significant down-regulation of CD11b expression was associated with the reduced phagocytic functions of peritoneal and lung macrophages. This severe immuno-toxicity phenotype was not observed in ATO-treated ATF4(+/-) heterozygous mice. To confirm these observations, we demonstrated in Raw 264.7 cells that ATF4 knock-down rescues ATO-mediated impairment of macrophage functions including cytokine production, bacterial engulfment and clearance of engulfed bacteria. Sustained activation of ATF4 by ATO in macrophages induces apoptosis, while diminution of ATF4 expression protects against ATO-induced apoptotic cell death. Raw 264.7 cells treated with ATO also manifest dysregulated Ca(++) homeostasis. ATO induces Ca(++)-dependent calpain-1 and caspase-12 expression which together regulated macrophage apoptosis. Additionally, apoptosis was also induced by mitochondria-regulated pathway. Restoring ATO-impaired Ca(++) homeostasis in ER/mitochondria by treatments with the inhibitors of inositol 1,4,5-trisphosphate receptor (IP3R) and voltage-dependent anion channel (VDAC) attenuate innate immune functions of macrophages. These studies identify a novel role for ATF4 in underlying pathogenesis of macrophage dysregulation and immuno-toxicity of arsenic.
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Ritesh K
authors.initials: RK
authors.lastname: Srivastava
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Changzhao
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Elmets
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Harrod
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: treena@uab.edu.
authors.forename: Jessy S
authors.initials: JS
authors.lastname: Deshane
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: mathar@uab.edu.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D006706:Homeostasis; D007113:Immunity, Innate / Q000187:drug effects*; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010087:Oxides / Q000633:toxicity*
chemical_list: D001152:Arsenicals; D016207:Cytokines; D010087:Oxides; D051701:Activating Transcription Factor 4; D000077237:Arsenic Trioxide; D002118:Calcium
keywords: ATF4; Apoptosis; Arsenic; Ca(++) homeostasis; Macrophage functions; UPR