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

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

  • Wenqiang Song
  • Jielin Xu
  • J. Luke Postoak
  • Feixiong Cheng
  • Jennifer Martinez
  • Jianhua Zhang
  • Lan Wu
  • Luc Van Kaer

Detail(s)

Original languageEnglish
Pages (from-to)2024–2039
Journal / PublicationCellular and Molecular Immunology
Volume18
Issue number8
Online published24 Nov 2020
Publication statusPublished - Aug 2021
Externally publishedYes

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.

Citation Format(s)

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; Van Kaer, Luc.

In: Cellular and Molecular Immunology, Vol. 18, No. 8, 08.2021, p. 2024–2039.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review