Pon1 Deficiency Promotes Trem2 Pathway-Mediated Microglial Phagocytosis and Inhibits Pro-inflammatory Cytokines Release In Vitro and In Vivo
Pon1 Deficiency Promotes Trem2 Pathway-Mediated Microglial Phagocytosis and Inhibits Pro-inflammatory Cytokines Release In Vitro and In Vivo
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DOI：
10.1007/s12035-022-02827-1
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发表时间：
2022-05-19
影响因子：
5.1
通讯作者：
Zhang，Lianfeng
中科院分区：
文献类型：
--
作者：
Zhang，Li;Dong，Wei;Zhang，Lianfeng
Paraoxonase 1 (PON1) plays an anti-inflammatory role in the cardiovascular system. Levels of serum PON1 and polymorphisms in this gene were linked to Alzheimer’s disease (AD) and Parkinson disease (PD), but its function in the neuroimmune system and AD is not clear. To address this issue, we usedPon1knockout rats previously generated by our lab to investigate the role of Pon1 in microglia. Knockout ofPon1in rat brain tissues protected against LPS-induced microglia activation. Pon1 deficiency in rat primary microglia increased Trem2 (triggering receptor expressed in myeloid cells 2) expression, phagocytosis, and IL-10 (M2-phenotype marker) release, but decreased production of pro-inflammatory cytokines such as IL-1β, IL-6, and IL-18 especially TNF-α (M1-phenotype markers) induced by LPS. Pon1 deficiency in rat primary microglia activated Trem2 pathway but decreased LPS-induced ERK activation. The phagocytosis-promoting effect ofPon1knockout could be reversed by administration of recombinant PON1 protein. The interaction between PON1 and TREM2 was verified by co-immunoprecipitation (co-IP) using rat brain tissues or over-expressed BV2 cell lysates, which might be involved in lysosomal localization of TREM2. Furthermore,Pon1knockout also enhanced microglial phagocytosis and clearance of exogenous Aβ by an intrahippocampal injection and decrease the transcription of cytokines such as IL-1β, IL-6, and TNF-α in vivo. These results suggest that Pon1 knockout facilitates microglial phagocytosis and inhibits the production of proinflammatory cytokines both in vivo and in vitro, in which the interaction between Pon1 and Trem2 may be involved. These findings provide novel insights into the role of PON1 in neuroinflammation and highlight TREM2 as a potential target for Alzheimer’s disease therapy.
