First Author | Lu R | Year | 2012 |
Journal | PLoS Pathog | Volume | 8 |
Issue | 4 | Pages | e1002597 |
PubMed ID | 22496641 | Mgi Jnum | J:195394 |
Mgi Id | MGI:5478702 | Doi | 10.1371/journal.ppat.1002597 |
Citation | Lu R, et al. (2012) CEACAM1 negatively regulates IL-1beta production in LPS activated neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex. PLoS Pathog 8(4):e1002597 |
abstractText | LPS-activated neutrophils secrete IL-1beta 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-1beta 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-1beta secretion in neutrophils. The absence of this regulation in Ceacam1(-)/(-) neutrophils led to hyper production of IL-1beta in response to LPS. The hyper production of IL-1beta 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-1beta production by the inflammasome. Thus, CEACAM1 fine-tunes IL-1beta production in LPS treated neutrophils, explaining why the additional utilization of CEACAM1 as a pathogen receptor would further inhibit inflammation. |