Synaptotagmin‐11 regulates immune functions of microglia in vivo

Author:

Zhang Feifan1,Yang Dong2,Li Jingchen1,Du Cuilian1,Sun Xinran2,Li Wanru1,Liu Fengwei1,Yang Yiwei2,Li Yuhong1,Fu Lei2,Li Rena13,Zhang Claire Xi12ORCID

Affiliation:

1. Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders Capital Medical University Beijing China

2. Academy of Pharmacy Xi'an Jiaotong‐Liverpool University Suzhou China

3. Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital and Beijing Institute of Brain Disorders Capital Medical University Beijing China

Abstract

AbstractMembrane trafficking pathways mediate key microglial activities such as cell migration, cytokine secretion, and phagocytosis. However, the underlying molecular mechanism remains poorly understood. Previously, we found that synaptotagmin‐11 (Syt11), a non‐Ca2+‐binding Syt associated with Parkinson's disease (PD) and schizophrenia, inhibits cytokine release and phagocytosis in primary microglia. Here we reported the in vivo function of Syt11 in microglial immune responses using an inducible microglia‐specific Syt11‐conditional‐knockout (cKO) mouse strain. Syt11‐cKO resulted in activation of microglia and elevated mRNA levels of IL‐6, TNF‐α, IL‐1β, and iNOS in various brain regions under both resting state and LPS‐induced acute inflammation state in adult mice. In a PD mouse model generated by microinjection of preformed α‐synuclein fibrils into the striatum, a reduced number of microglia migrated toward the injection sites and an enhanced phagocytosis of α‐synuclein fibrils by microglia were found in Syt11‐cKO mice. To understand the molecular mechanism of Syt11 function, we identified its direct binding proteins vps10p‐tail‐interactor‐1a (vti1a) and vti1b. The linker domain of Syt11 interacted with both proteins and a peptide derived from it competitively inhibited the interaction of Syt11 with vti1a/vti1b in vitro and in cells. Importantly, application of this peptide induced more cytokine secretion in wild‐type microglia upon LPS treatment, phenocopying defects in Syt11 knockdown cells. Altogether, we propose that Syt11 inhibits microglial activation in vivo and regulates cytokine secretion through interactions with vti1a and vti1b.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Cellular and Molecular Neuroscience,Biochemistry

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