CEACAM1 negatively regulates IL-1β production in LPS activated neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex

Lps-activated neutrophils secrete il-1β by activation of tlr-4. based on studies in macrophages,it is likely that ros and lysosomal destabilization regulated by syk activation may also be involved. since neutrophils have abundant expression of the itim-containing co-receptor ceacam1 and gram-negative bacteria such as neisseria utilize ceacam1 as a receptor that inhibits inflammation,we hypothesized that the overall production of il-1β in lps treated neutrophils may be negatively regulated by ceacam1. we found that lps treated neutrophils induced phosphorylation of syk resulting in the formation of a complex including tlr4,p-syk,and p-ceacam1,which in turn,recruited the inhibitory phosphatase shp-1. lps treatment leads to ros production,lysosomal damage,caspase-1 activation and il-1β secretion in neutrophils. the absence of this regulation in ceacam1-/- neutrophils led to hyper production of il-1β in response to lps. the hyper production of il-1β was abrogated by in vivo reconstitution of wild type but not itim-mutated ceacam1 bone marrow stem cells. blocking syk activation by kinase inhibitors or rnai reduced syk phosphorylation,lysosomal destabilization,ros production,and caspase-1 activation in ceacam1-/- neutrophils. we conclude that lps treatment of neutrophils triggers formation of a complex of tlr4 with psyk and pceacam1,which upon recruitment of shp-1 to the itims of pceacam1,inhibits il-1β production by the inflammasome. thus,ceacam1 fine-tunes il-1β production in lps treated neutrophils,explaining why the additional utilization of ceacam1 as a pathogen receptor would further inhibit inflammation. © 2012 lu et al.