A pathogenic role for ER stress-induced autophagy and ER chaperone GRP78/BiP in T lymphocyte systemic lupus erythematosus

Abstract

Abnormal regulation of ER stress and apoptosis has been implicated in autoimmune disorders. Particularly, ER stress-induced autophagy and the role of GRP78, or BiP in T lymphocyte survival and death in SLE are poorly understood. This study investigated the pathogenic roles of ER stress-induced autophagy and GRP78/BiP in apoptosis of T lymphocytes. We compared spontaneous and induced autophagy and apoptosis of T lymphocytes in healthy donors and patients with SLE. The molecular mechanism of altered autophagy and apoptosis was investigated in T lymphocytes transfected with siRNA for beclin 1 and CHOP and T lymphocytes overexpressing GRP78. Decreased autophagy and increased apoptosis in response to TG-induced ER stress were observed in lupus T lymphocytes. GRP78 and ER stress-signaling molecules, such as PERK, p-eIF2α, IRE1, and ATF6 decreased, whereas CHOP levels increased in lupus T cells in response to TG. The levels antiapoptotic molecules, Bcl-2 and Bcl-XL decreased, whereas the proapoptotic molecules, Bax and caspase 6, increased in lupus T cells. The TG-induced ER stress altered autophagy and apoptosis, which in turn, led to abnormal T cell homeostasis with increased apoptotic T cell death. We hypothesize that aberrant autophagy of T lymphocytes as a result of ER stress and decreased GRP78 expression is involved in the pathogenesis of SLE and might serve as important therapeutic targets.

Cocaine induces astrocytosis through ER stress-mediated activation of autophagy

“…14,34,44 Several reports have implicated a central role for ER stress in the induction of autophagy in the pathogenesis of various neurodegenerative diseases mediated by diverse stressors. [45][46][47][48][49][50] In the current study, we demonstrate for the first time a molecular link between ER stress-mediated activation of autophagy and the induction of astrogliosis that is accompanied with the release of proinflammatory cytokines in cocainetreated human astrocytes.…”

Endoplasmic Reticulum Stress and Apoptosis Triggered by Sub-Chronic Lead Exposure in Mice Spleen: a Histopathological Study

“…In agreement with these studies, we localized splenic proapoptotic markers in RP and WP induced by Pb exposure. Interestingly, a peculiar link between ER stress and abnormal apoptosis was reported in auto-immune disorders and in patients of systemic lupus erythematosus [72]. In light of these data, increase of ER stress and pro-apoptotic cleaved caspase-3 markers in WP, after Pb treatment, could reflect an impairment of immune functions.…”

Immune thrombocytopenia induces autophagy and suppresses apoptosis in megakaryocytes

“…Houwerzijl et al (5) demonstrated increased vacuoles, plasma membrane thickening and chromatin condensation in the mitochondria and endoplasmic reticulum (ER) of ITP megakaryocytes. This may result in endoplasmic reticulum stress, leading to autophagy (6,7). Autophagy is a biological process, where cytoplasmic macromolecules self-degrade through the lysosomal pathway (8).…”