Synaptotagmin‐11 inhibits cytokine secretion and phagocytosis in microglia

Abstract

Cytokine secretion and phagocytosis are key functions of activated microglia. However, the molecular mechanisms underlying their regulation in microglia remain largely unknown. Here, we report that synaptotagmin-11 (Syt11), a non-Ca -binding Syt implicated in Parkinson disease and schizophrenia, inhibits cytokine secretion and phagocytosis in microglia. We found Syt11 expression in microglia in brain slices and primary microglia. Interestingly, Syt11-knockdown (KD) increased cytokine secretion and NO release in primary microglia both in the absence and presence of lipopolysaccharide. NF-κB was activated in untreated KD microglia together with enhanced synthesis of IL-6, TNF-α, IL-1β, and iNOS. When the release capacity was assessed by the ratio of extracellular to intracellular levels, only the IL-6 and TNF-α secretion capacity was increased in Syt11-KD cells, suggesting that Syt11 specifically regulates conventional secretion. Consistently, Syt11 localized to the trans-Golgi network and recycling endosomes. In addition, Syt11 was recruited to phagosomes and its deficiency enhanced microglial phagocytosis. All the KD phenotypes were rescued by expression of an shRNA-resistant Syt11, while overexpression of Syt11 suppressed cytokine secretion and phagocytosis. Importantly, Syt11 also inhibited microglial phagocytosis of α-synuclein fibrils, supporting its association with Parkinson disease. Taken together, we propose that Syt11 suppresses microglial activation under both physiological and pathological conditions through the inhibition of cytokine secretion and phagocytosis.

Glial phagocytic clearance in Parkinson’s disease

“…Syt11 , the encoding gene for Synaptotagmin-11 (Syt11) is contained within a genome wide associated study-identified locus implicated in PD risk [92]. Syt11 localized to the TGN and recycling endosomes and appears to be involved in cytokine secretion and phagocytosis in microglia [93]. Syt11 was recruited to phagosomes and Syt11 deficiency inhibits microglial phagocytosis of α-syn fibrils, supporting its association with PD [93].…”

“…Syt11 localized to the TGN and recycling endosomes and appears to be involved in cytokine secretion and phagocytosis in microglia [93]. Syt11 was recruited to phagosomes and Syt11 deficiency inhibits microglial phagocytosis of α-syn fibrils, supporting its association with PD [93].…”

Synaptotagmin-11 mediates a vesicle trafficking pathway that is essential for development and synaptic plasticity

“…Recent studies have proposed that in the substantia nigra pars compacta, Syt11 is a mediator of neurotoxicity that interacts with Parkin and regulates the pools of dopaminergic vesicles by inhibiting endocytosis (Wang et al 2018). Syt11 has also been proposed to inhibit cytokine secretion and phagocytosis in glia (Du et al 2017), but its precise role in development and function of neural circuits has remained largely unknown. Curiously, constitutive knockout mice lacking Syt4, a close Syt11 homolog, have a normal life span but exhibit enhanced synaptic potentiation and deficits in motor coordination and hippocampus-dependent memory (Ferguson et al 2004;Dean et al 2009).…”

CSF proteomics of patients with hydrocephalus and subarachnoid haemorrhage

“…Augurin levels were significantly lower in SAH patients, but we found no significant difference between good and poor outcome patients, nor did we find significant changes with time. Synaptotagmin-11 regulates repair of injured astrocytes following acute brain injury [33] and also suppresses microglial activation under both physiological and pathological conditions, through the inhibition of cytokine secretion and phagocytosis [34]. In this study, synaptotagmin-11 was found to be decreased in good outcome patients compared with healthy controls, but there was no significant difference between the good and poor outcome group.…”