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

Sanja Arandjelovic, Justin S A Perry, Christopher Lucas, Kristen K Penberthy, Tae-Hyoun Kim, Ming Zhou, Dorian A Rosen, Tzu-Ying Chuang, Alexandra M Bettina , Laura S Shankman, Amanda H Cohen, Claude Gaultier, Thomas P Conrads, Minsoo Kim, Michael R Elliott, Kodi S. Ravichandran

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Rheumatoid arthritis is an inflammatory disease of the synovial joints that affects ~1% of the human population, with severe distress due to progressive joint inflammation and deformation. When addressing the links between specific components of the apoptotic cell clearance machinery and human disease, we noted a correlation between single nucleotide polymorphisms (SNPs) in ELMO1, DOCK2, and RAC1 genes and rheumatoid arthritis. ELMO1 is a cytoplasmic adapter protein that associates with DOCK2 and RAC1 to promote cytoskeletal reorganization needed for apoptotic cell uptake by phagocytes. We initially hypothesized that, since ELMO1 is linked to apoptotic cell clearance, loss of ELMO1 would lead to increased inflammation in arthritis. Contrary to the accumulation of apoptotic cells and greater disease severity that we predicted, we observed significantly reduced joint inflammation in two models of arthritis in mice lacking ELMO1. Using genetic and cell biological approaches in vivo and ex vivo, we determined that ELMO1 deficiency significantly reduces neutrophil recruitment to inflamed joints, but does not result in general inhibition of inflammatory responses. Through proteomic analyses, we find that ELMO1 protein associates with cellular receptors that contribute to neutrophil function in arthritis, and regulates C5a and LTB4 receptor-mediated activation and early neutrophil recruitment to the joints. Neutrophil-specific transcriptomics show that ELMO1 modulates neutrophil-specific gene expression that includes genes with known linkages to human arthritis. Finally, 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 LTB4. These data identify key ‘non-canonical’ roles for engulfment machinery components in arthritis, and ELMO1 as an important regulator of specific neutrophil receptors and signaling linked to arthritis.

Original languageEnglish
JournalNature Immunology
Early online date14 Jan 2019
DOIs
Publication statusE-pub ahead of print - 14 Jan 2019

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