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

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

  • Cell Mol Immunol. 2021 Aug;18(8):2024-2039. doi: 10.1038/s41423-020-00589-1.
Guan Yang 1,  Wenqiang Song 1,  Jielin Xu 2,  J Luke Postoak 1,  Feixiong Cheng 2 3 4,  Jennifer Martinez 5,  Jianhua Zhang 6 7,  Lan Wu 1,  Luc Van Kaer 8
Affiliations

Affiliations

  • 1 Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
  • 2 Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
  • 3 Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA.
  • 4 Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
  • 5 Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, 27709, USA.
  • 6 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
  • 7 Birmingham Veterans Affairs Medical Center, Birmingham, AL, 35233, USA.
  • 8 Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. luc.van.kaer@vanderbilt.edu.
PMID: 33235386 DOI: 10.1038/s41423-020-00589-1
Abstract

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-1β production. 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.

Keywords

Autophagy; Experimental autoimmune encephalomyelitis; IL-1β; Myeloid cells; PIK3C3.

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