The Systemic Lupus Erythematosus-Associated Single Nucleotide Polymorphism rs1143678 in Integrin {alpha}M Cytoplasmic Tail Generates a 14-3-3{zeta} Binding Site That Is Proinflammatory [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

The leukocyte integrin α_Mβ₂ (CR3 or Mac-1) has both proinflammatory and immune regulatory functions. Genome-wide association studies have identified several ITGAM (α_M subunit) single nucleotide polymorphisms that are associated with systemic lupus erythematosus. The single nucleotide polymorphism rs1143678 substitutes Pro¹¹⁴⁶ for Ser in the integrin α_M 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 α_Mβ₂–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-α in integrin α_M(PS)β₂ BMDMs were significantly higher than those of integrin α_M(wild-type)β₂ BMDMs, and they showed faster kinetics of Erk1/2 activation through the src family kinase(s)–Syk signaling pathway. Integrin α_M(PS)β₂ BMDMs also exhibited higher levels of active RhoA and phagocytic activity. Mechanistically, P1146S substitution in the α_M cytoplasmic tail generates a noncanonical 14-3-3 binding site that modulates integrin α_M(PS)β₂ outside-in signaling.

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