TY - JOUR
T1 - A noncanonical role for the engulfment gene ELMO1 in neutrophils that promotes inflammatory arthritis
AU - Arandjelovic, Sanja
AU - Perry, Justin S.A.
AU - Lucas, Christopher D.
AU - Penberthy, Kristen K.
AU - Kim, Tae Hyoun
AU - Zhou, Ming
AU - Rosen, Dorian A.
AU - Chuang, Tzu Ying
AU - Bettina, Alexandra M.
AU - Shankman, Laura S.
AU - Cohen, Amanda H.
AU - Gaultier, Alban
AU - Conrads, Thomas P.
AU - Kim, Minsoo
AU - Elliott, Michael R.
AU - Ravichandran, Kodi S.
N1 - Funding Information:
The authors thank members of the Ravichandran laboratory for discussions and critical reading of the manuscript, A. Criss and A. Smirnov for human neutrophils, S. T. Fleury for assistance with neutrophil purification, and K. Koster for assistance with bone marrow preparations. This work is supported by grants to K.S.R. from NIGMS R35GM122542, NIMH (MH096484), NHLBI (P01HL120840), NICHD (HD07498), and the Center for Cell Clearance/University of Virginia School of Medicine, and the Odysseus Award from the FWO, Belgium, to M.R.E. from NIAID (AI114554), to M.K. from NIAID (P01 AI102851), and to A.G. (NS083542 and NS101281). Additional support was provided by the Philip S. Magaram, Esq. Research Award from the Arthritis Foundation to S.A.. J.S.A.P. is supported by a Mark Foundation award from the Cancer Research Institute and a postdoctoral enrichment award from Burroughs Wellcome and was previously supported by a postdoctoral fellowship through a T32 Cancer Training Grant. C.D.L. is supported by an award from The Wellcome Trust (206566/Z/17/Z). L.S.S. is supported by the Roaring Fork Valley Postdoctoral Research Fellowship (PF-17-098-01-CSM) from the American Cancer Society, and K.K.P. is supported by an NHLBI F30 award (F30 HL126385) and was previously supported by an NIH T32 Immunology Training Grant (T32 AI007496).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85060109852&partnerID=8YFLogxK
U2 - 10.1038/s41590-018-0293-x
DO - 10.1038/s41590-018-0293-x
M3 - Article
C2 - 30643265
AN - SCOPUS:85060109852
SN - 1529-2908
VL - 20
SP - 141
EP - 151
JO - Nature Immunology
JF - Nature Immunology
IS - 2
ER -