Pik3c3 deficiency in myeloid cells imparts partial resistance to experimental autoimmune encephalomyelitis associated with reduced IL-1β production

Yang, Guan; Song, Wenqiang; Xu, Jielin; Postoak, J. Luke; Cheng, Feixiong; Martinez, Jennifer; Zhang, Jianhua; Wu, Lan; Kaer, Luc Van

doi:10.1038/s41423-020-00589-1

Cited by 15 publications

(13 citation statements)

References 71 publications

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“…Similarly, our previous study revealed decreased p62 expression in spleen tissue and ongoing autophagy flux in splenic CD11b + myeloid cells and CD4 + T cells of mice with EAE (22). We also observed increased expression of genes involved in different stages of the autophagic process (initiation: Ulk1, Ulk2, and Rb1cc1; nucleation: Pik3c3 and Becn1; elongation: Atg3, Atg5, and Atg7; and fusion: Gabarap and Map1lc3bp) in monocyte-derived myeloid cells obtained from the CNS of mice with EAE (22).…”

Section: Autophagy Is Altered In Eaesupporting

confidence: 73%

“…Another study found reduced levels of the autophagy substrate sequestosome (SQSTM1, also known as p62) in the spinal cord at all stages of EAE ( 21 ), whereas LC3-II levels were increased at the early disease stage and returned to normal levels at the peak of disease ( 21 ). Similarly, our previous study revealed decreased p62 expression in spleen tissue and ongoing autophagy flux in splenic CD11b + myeloid cells and CD4 + T cells of mice with EAE ( 22 ). We also observed increased expression of genes involved in different stages of the autophagic process (initiation: Ulk1 , Ulk2 , and Rb1cc1; nucleation: Pik3c3 and Becn1 ; elongation: Atg3 , Atg5 , and Atg7 ; and fusion: Gabarap and Map1lc3bp ) in monocyte-derived myeloid cells obtained from the CNS of mice with EAE ( 22 ).…”

Section: Autophagy Is Altered In Eaesupporting

confidence: 72%

“…Treatment with chloroquine, which blocks the fusion of autophagosomes with lysosomes, at different stages of EAE development delays disease onset or severity (21,71). Similarly, we recently observed delayed EAE disease progression in mice treated with a selective PIK3C3 inhibitor, SAR405 (22). Pretreatment of mesenchymal stem cells with the PtdIns3K FIGURE 2 | Autophagy and LAP share several key molecular regulators and machinery.…”

Section: Autophagy Inhibitionmentioning

confidence: 71%

“…This protection was not due to alterations in the induction of pathogenic T cells, because mice with myeloid cellspecific Pik3c3 or Atg7 deficiency also exhibited reduced EAE after adoptive transfer of myelin-specific T cells from WT animals (22,44). This attenuated EAE phenotype was associated with changes in many physical and cellular processes, including reduced breakdown of blood-spinal cord barrier permeability (43), decreased CNS immune cell infiltration (22,43), reduced IL-1b production by myeloid cells (22), or stalling of Th17 cells in the lung en route to the CNS (44). Interestingly, no impairment of peripheral antigen-specific T cell activation was observed in myeloid cell-specific Pik3c3-, Atg5-, or Atg7-deficient mice (22,43,44).…”

Section: Macrophages and Microgliamentioning

confidence: 98%

“…Selective Pik3c3 , Atg5 , or Atg7 deficiency in myeloid cells using a Lyz2-Cre transgene resulted in attenuated EAE disease severity ( 22 , 43 , 44 ). This protection was not due to alterations in the induction of pathogenic T cells, because mice with myeloid cell-specific Pik3c3 or Atg7 deficiency also exhibited reduced EAE after adoptive transfer of myelin-specific T cells from WT animals ( 22 , 44 ).…”

Section: Autophagy Manipulation In Immune Cells Alters Eae Pathogenesismentioning

confidence: 99%

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Therapeutic Targeting of Immune Cell Autophagy in Multiple Sclerosis: Russian Roulette or Silver Bullet?

Yang

Kaer

2021

Front. Immunol.

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which the immune system damages the protective insulation surrounding nerve fibers that project from neurons. The pathological hallmark of MS is multiple areas of myelin loss accompanied by inflammation within the CNS, resulting in loss of cognitive function that ultimately leads to paralysis. Recent studies in MS have focused on autophagy, a cellular self-eating process, as a potential target for MS treatment. Here, we review the contribution of immune cell autophagy to the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the prototypic animal model of MS. A better understanding of the role of autophagy in different immune cells to EAE might inform the development of novel therapeutic approaches in MS and other autoimmune and inflammatory diseases.

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Section: Autophagy Is Altered In Eaesupporting

confidence: 73%

Section: Autophagy Is Altered In Eaesupporting

confidence: 72%

Section: Autophagy Inhibitionmentioning

confidence: 71%

Section: Macrophages and Microgliamentioning

confidence: 98%

Section: Autophagy Manipulation In Immune Cells Alters Eae Pathogenesismentioning

confidence: 99%

See 3 more Smart Citations

Therapeutic Targeting of Immune Cell Autophagy in Multiple Sclerosis: Russian Roulette or Silver Bullet?

Yang

Kaer

2021

Front. Immunol.

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Modulation of the immunity and inflammation by autophagy

Gan

Zhang

et al. 2023

MedComm

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Autophagy, a highly conserved cellular self‐degradation pathway, has emerged with novel roles in the realms of immunity and inflammation. Genome‐wide association studies have unveiled a correlation between genetic variations in autophagy‐related genes and heightened susceptibility to autoimmune and inflammatory diseases. Subsequently, substantial progress has been made in unraveling the intricate involvement of autophagy in immunity and inflammation through functional studies. The autophagy pathway plays a crucial role in both innate and adaptive immunity, encompassing various key functions such as pathogen clearance, antigen processing and presentation, cytokine production, and lymphocyte differentiation and survival. Recent research has identified novel approaches in which the autophagy pathway and its associated proteins modulate the immune response, including noncanonical autophagy. This review provides an overview of the latest advancements in understanding the regulation of immunity and inflammation through autophagy. It summarizes the genetic associations between variants in autophagy‐related genes and a range of autoimmune and inflammatory diseases, while also examining studies utilizing transgenic animal models to uncover the in vivo functions of autophagy. Furthermore, the review delves into the mechanisms by which autophagy dysregulation contributes to the development of three common autoimmune and inflammatory diseases and highlights the potential for autophagy‐targeted therapies.

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