PON1 deficiency promotes TREM2 pathway-mediated microglial phagocytosis and inhibits LPS-induced pro-inflammatory cytokines release

Abstract Background Paraoxonase 1 (PON1), an HDL-associated enzyme, plays an anti-inflammatory role in the cardiovascular system. Levels of serum PON1 and polymorphisms in this gene were linked to Alzheimer disease (AD) and Parkinson disease (PD), but its function in the neuroimmune system and AD are not clear. Methods PON1 knockout rats previously generated by our lab were used to investigate the role of PON1 in microglia. Wild type (WT) rats and PON1 knockout (KO) rats were injected with lipopolysaccharide (LPS, 5 or 20 mg/kg) and the survival rates were compared. Microglia on the sections of rat brain tissues were immunostained with anti-Iba1 antibody and the microglia morphology was compared. The phagocytosis, cytokines release and transcriptome of primary microglia cells treated with or without LPS were analyzed. The interactions between PON1 and TREM2 were detected by co-immunoprecipitation (co-IP) using rat brain tissues or over-expressed BV2 cell lysates. Results The expression of PON1 was detected in human and rat brain tissues and rat primary microglia. Knockout of PON1 in rat brain tissues protected against LPS-induced lethality by decreasing TNF-α expression. PON1 knockout in microglia increased TREM2 (triggering receptor expressed in myeloid cells 2) expressing and phagocytosis, but decreased production of pro-inflammatory cytokines such as IL-1β, IL-6, IL-12, IL-18 especially TNF-α (M1-phenotype markers) and increased IL-10 (M2-phenotype marker) release induced by LPS. PON1 knockout activated TREM2 pathway but decreased LPS-induced ERK activation. The phagocytosis promoting effect was reversed by administration of recombinant PON1 protein. The interaction between PON1 and TREM2 was verified and was associated with the localization of TREM2 in lysosomes. Conclusions These results suggest an inhibitory role of PON1 in microglial phagocytosis dependent on its interaction with TREM2. These findings provide novel insights into the role of PON1 in neuroinflammation and highlight TREM2 as a potential target for Alzheimer’s disease therapy.