Carcinoembryonic antigen-related cell adhesion molecule 1 down regulates Syk coupled neutrophil NLRP3 inflammasome activation through ITIM and the recruitment of SHP-1 (157.12)

Abstract

Abstract IL-1β is a critical pro-inflammatory cytokine produced by innate immune cells, and is regulated by the inflammasome. Recently thioredoxin -interacting protein (TXNIP) has been shown to associate with and activate the Nod-like receptor protein 3(NLRP3) inflammosome in a ROS-sensitive manner. We have found LPS induced the NLRP3 inflammasome activation in neutrophils was dependent on ROS production and lysosomal damage, both of which were regulated by spleen tyrosine kinase (Syk).We have demonstrated LPS induced phosphorylation of Syk and formation of a complex platform including Toll -like receptor 4(TLR4), TXNIP and p-Syk, to facilitate ROS production the inflammosome activation. We also found that carcinoembryonic antigen-related cell adhesion molecule 1(CEACAM1) associated with TLR4 ,TXNIP and p-Syk complex in response to LPS. IL-1β, pro-caspase-1, ROS and lysosomal destabilization are enhanced in neutrophils from ceacam1-/- mice. CEACAM negatively regulates phosphorylation of Syk and the inflammosome activation by recruiting phosphatase SHP-1 through CEACAM1’s (immunoreceptor tyrosine-based inhibition motif) ITIMs. Pharmaceutical inhibition of Syk activation or knock down of Syk attenuated Syk phosphorylation and the inflammosome activation in ceacam1-/- neutrophils. Reconstitution of CEACAM1 restores inflammasome activation to normal level. Therefore, we identify CEACAM1 as a negative regulator of the Syk coupled NLRP3 inflammasome activation.