The PIK3C3/VPS34 subunit of the class III phosphatidylinositol 3-kinase(PtdIns3K)complex plays a role in both canonical and noncanonical autophagy,key processes that control immune-cell responsiveness to a variety of ...The PIK3C3/VPS34 subunit of the class III phosphatidylinositol 3-kinase(PtdIns3K)complex plays a role in both canonical and noncanonical autophagy,key processes that control immune-cell responsiveness to a variety of stimuli.Our previous studies found that PIK3C3 is a critical regulator that controls the development,homeostasis,and function of dendritic and T cells.In this study,we investigated the role of PIK3C3 in myeloid cell biology using myeloid cell-specific Pik3c3-deficient mice.We found that Pik3c3-deficient macrophages express increased surface levels of major histocompatibility complex(MHC)class I and class II molecules.In addition,myeloid cell-specific Pik3c3 ablation in mice caused a partial impairment in the homeostatic maintenance of macrophages expressing the apoptotic cell uptake receptor TIM-4.Pik3c3 deficiency caused phenotypic changes in myeloid cells that were dependent on the early machinery(initiation/nucleation)of the classical autophagy pathway.Consequently,myeloid cell-specific Pik3c3-deficient animals showed significantly reduced severity of experimental autoimmune encephalomyelitis(EAE),a primarily CD4^(^(+))T-cell-mediated mouse model of multiple sclerosis(MS).This disease protection was associated with reduced accumulation of myelin-specific CD4^(^(+))T cells in the central nervous system and decreased myeloid cell IL-1βproduction.Further,administration of SAR405,a selective PIK3C3 inhibitor,delayed disease progression.Collectively,our studies establish PIK3C3 as an important regulator of macrophage functions and myeloid cell-mediated regulation of EAE.Our findings also have important implications for the development of small-molecule inhibitors of PIK3C3 as therapeutic modulators of MS and other autoimmune diseases.展开更多
基金Work in the authors’lab was supported by grants from the NIH(AI139046 to L.V.K.and 1ZIAES10328601 to J.M.)the National Multiple Sclerosis Society(60006625 to L.V.K.)+3 种基金Core Services were performed through the Vanderbilt Digestive Disease Research Center(NIH grant P30DK058404)the Vanderbilt Ingram Cancer Center(NIH grant P30CA68485)the Vanderbilt Diabetes Research and Training Center(NIH grant P60DK020593)J.L.P.was supported by predoctoral NIH training grants(T32HL069765 and T32AR059039).
文摘The PIK3C3/VPS34 subunit of the class III phosphatidylinositol 3-kinase(PtdIns3K)complex plays a role in both canonical and noncanonical autophagy,key processes that control immune-cell responsiveness to a variety of stimuli.Our previous studies found that PIK3C3 is a critical regulator that controls the development,homeostasis,and function of dendritic and T cells.In this study,we investigated the role of PIK3C3 in myeloid cell biology using myeloid cell-specific Pik3c3-deficient mice.We found that Pik3c3-deficient macrophages express increased surface levels of major histocompatibility complex(MHC)class I and class II molecules.In addition,myeloid cell-specific Pik3c3 ablation in mice caused a partial impairment in the homeostatic maintenance of macrophages expressing the apoptotic cell uptake receptor TIM-4.Pik3c3 deficiency caused phenotypic changes in myeloid cells that were dependent on the early machinery(initiation/nucleation)of the classical autophagy pathway.Consequently,myeloid cell-specific Pik3c3-deficient animals showed significantly reduced severity of experimental autoimmune encephalomyelitis(EAE),a primarily CD4^(^(+))T-cell-mediated mouse model of multiple sclerosis(MS).This disease protection was associated with reduced accumulation of myelin-specific CD4^(^(+))T cells in the central nervous system and decreased myeloid cell IL-1βproduction.Further,administration of SAR405,a selective PIK3C3 inhibitor,delayed disease progression.Collectively,our studies establish PIK3C3 as an important regulator of macrophage functions and myeloid cell-mediated regulation of EAE.Our findings also have important implications for the development of small-molecule inhibitors of PIK3C3 as therapeutic modulators of MS and other autoimmune diseases.
