| First Author | Ong LT | Year | 2017 |
| Journal | J Immunol | Volume | 198 |
| Issue | 2 | Pages | 883-894 |
| PubMed ID | 27974454 | Mgi Jnum | J:247876 |
| Mgi Id | MGI:5925623 | Doi | 10.4049/jimmunol.1601447 |
| Citation | Ong LT, et al. (2017) The Systemic Lupus Erythematosus-Associated Single Nucleotide Polymorphism rs1143678 in Integrin alphaM Cytoplasmic Tail Generates a 14-3-3zeta Binding Site That Is Proinflammatory. J Immunol 198(2):883-894 |
| abstractText | The leukocyte integrin alphaMbeta2 (CR3 or Mac-1) has both proinflammatory and immune regulatory functions. Genome-wide association studies have identified several ITGAM (alphaM subunit) single nucleotide polymorphisms that are associated with systemic lupus erythematosus. The single nucleotide polymorphism rs1143678 substitutes Pro1146 for Ser in the integrin alphaM cytoplasmic tail. A detailed functional characterization of this substitution is lacking. Using transfected human cell lines, reconstituted mouse bone marrow neutrophils, and bone marrow-derived macrophages (BMDMs), we showed that P1146S (PS) substitution promoted integrin alphaMbeta2-mediated adhesion, spreading, and migration of cells on iC3b and fibrinogen. In the presence of LPS together with iC3b or fibrinogen, the expression levels of IL-6 and TNF-alpha in integrin alphaM(PS)beta2 BMDMs were significantly higher than those of integrin alphaM(wild-type)beta2 BMDMs, and they showed faster kinetics of Erk1/2 activation through the src family kinase(s)-Syk signaling pathway. Integrin alphaM(PS)beta2 BMDMs also exhibited higher levels of active RhoA and phagocytic activity. Mechanistically, P1146S substitution in the alphaM cytoplasmic tail generates a noncanonical 14-3-3zeta binding site that modulates integrin alphaM(PS)beta2 outside-in signaling. |
