title: Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption.
abstract: Arsenic exposure is known to disrupt innate immune functions in humans and in experimental animals. In this study, we provide a mechanism by which arsenic trioxide (ATO) disrupts macrophage functions. ATO treatment of murine macrophage cells diminished internalization of FITC-labeled latex beads, impaired clearance of phagocytosed fluorescent bacteria and reduced secretion of pro-inflammatory cytokines. These impairments in macrophage functions are associated with ATO-induced unfolded protein response (UPR) signaling pathway characterized by the enhancement in proteins such as GRP78, p-PERK, p-eIF2α, ATF4 and CHOP. The expression of these proteins is altered both at transcriptional and translational levels. Pretreatment with chemical chaperon, 4-phenylbutyric acid (PBA) attenuated the ATO-induced activation in UPR signaling and afforded protection against ATO-induced disruption of macrophage functions. This treatment also reduced ATO-mediated reactive oxygen species (ROS) generation. Interestingly, treatment with antioxidant N-acetylcysteine (NAC) prior to ATO exposure, not only reduced ROS production and UPR signaling but also improved macrophage functions. These data demonstrate that UPR signaling and ROS generation are interdependent and are involved in the arsenic-induced pathobiology of macrophage. These data also provide a novel strategy to block the ATO-dependent impairment in innate immune responses.
authors: Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Ritesh K
authors: RK
authors: Srivastava
authors: Changzhao
authors: C
authors: Li
authors: Sandeep C
authors: SC
authors: Chaudhary
authors: Mary E
authors: ME
authors: Ballestas
authors: Craig A
authors: CA
authors: Elmets
authors: David J
authors: DJ
authors: Robbins
authors: Sadis
authors: S
authors: Matalon
authors: Jessy S
authors: JS
authors: Deshane
authors: Farrukh
authors: F
authors: Afaq
authors: David R
authors: DR
authors: Bickers
authors: Mohammad
authors: M
authors: Athar
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D010087:Oxides / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D056811:Unfolded Protein Response / Q000187:drug effects / Q000276:immunology*
chemical_list: D001152:Arsenicals; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D010087:Oxides; D017382:Reactive Oxygen Species; D000077237:Arsenic Trioxide
keywords: Innate immune function; Inorganic arsenic; Macrophage; PBA; ROS; UPR
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