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A noncanonical role for the engulfment gene ELMO1 in neutrophils that promotes inflammatory arthritis

Arandjelovic, S;Perry, JSA;Lucas, CD;Penberthy, KK;Kim, TH;Zhou, M;Rosen, DA;Chuang, TY;Bettina, AM;Shankman, LS;Cohen, AH;Gaultier, A;Conrads, TP;Kim, M;Elliott, MR;Ravichandran, KS;

Rheumatoid arthritis is characterized by progressive joint inflammation and affects ~1% of the human population. We noted single-nucleotide polymorphisms (SNPs) in the apoptotic cell-engulfment genes ELMO1, DOCK2, and RAC1 linked to rheumatoid arthritis. As ELMO1 promotes cytoskeletal reorganization during engulfment, we hypothesized that ELMO1 loss would worsen inflammatory arthritis. Surprisingly, Elmo1-deficient mice showed reduced joint inflammation in acute and chronic arthritis models. Genetic and cell-biology studies revealed that ELMO1 associates with receptors linked to neutrophil function in arthritis and regulates activation and early neutrophil recruitment to the joints, without general inhibition of inflammatory responses. Further, neutrophils from the peripheral blood of human donors that carry the SNP in ELMO1 associated with arthritis display increased migratory capacity, whereas ELMO1 knockdown reduces human neutrophil migration to chemokines linked to arthritis. These data identify ‘noncanonical’ roles for ELMO1 as an important cytoplasmic regulator of specific neutrophil receptors and promoter of arthritis.