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

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.

• Authors: Guan Yang, Wenqiang Song, Jielin Xu, J Luke Postoak, Feixiong Cheng, Jennifer Martinez, Jianhua Zhang, Lan Wu, Luc Van Kaer
• Journal: Cellular & molecular immunology (Cell Mol Immunol) Vol. 18 Issue 8 Pg. 2024-2039 (08 2021) ISSN: 2042-0226 [Electronic] China
• PMID: 33235386 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.

Chemical References

• Class III Phosphatidylinositol 3-Kinases
• PIK3C3 protein, mouse

Topics

• Animals
• Autophagy
• Class III Phosphatidylinositol 3-Kinases (metabolism)
• Encephalomyelitis, Autoimmune, Experimental
• Mice
• Mice, Inbred C57BL
• Myeloid Cells (metabolism)
• T-Lymphocytes (metabolism)