Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Video-Audio Media
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / immunology*
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Animals
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Apoptosis / immunology
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Arthritis, Experimental / diagnosis
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Arthritis, Experimental / genetics
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Arthritis, Experimental / immunology*
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Arthritis, Experimental / pathology
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Arthritis, Rheumatoid / diagnosis
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Arthritis, Rheumatoid / genetics
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Arthritis, Rheumatoid / immunology*
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Arthritis, Rheumatoid / pathology
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Chemotaxis / genetics
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Chemotaxis / immunology
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Collagen / immunology
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Complement C5a / immunology
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Complement C5a / metabolism
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Cytoplasm / immunology
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Cytoplasm / metabolism
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Disease Models, Animal
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Female
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Gene Expression Profiling
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Healthy Volunteers
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Humans
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Intravital Microscopy
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Joints / cytology
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Joints / immunology
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Leukotriene B4 / immunology
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Leukotriene B4 / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neutrophils / immunology*
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Neutrophils / metabolism
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Polymorphism, Single Nucleotide
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Proteomics
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Severity of Illness Index
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Signal Transduction / immunology
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Time-Lapse Imaging
Substances
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Adaptor Proteins, Signal Transducing
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ELMO1 protein, human
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ELMO1 protein, mouse
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Leukotriene B4
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Complement C5a
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Collagen