A noncanonical role for the engulfment gene ELMO1 in neutrophils that promotes inflammatory arthritis.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Apoptosis
/ immunology
Arthritis, Experimental
/ diagnosis
Arthritis, Rheumatoid
/ diagnosis
Chemotaxis
/ genetics
Collagen
/ immunology
Complement C5a
/ immunology
Cytoplasm
/ immunology
Disease Models, Animal
Female
Gene Expression Profiling
Healthy Volunteers
Humans
Intravital Microscopy
Joints
/ cytology
Leukotriene B4
/ immunology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neutrophils
/ immunology
Polymorphism, Single Nucleotide
Proteomics
Severity of Illness Index
Signal Transduction
/ immunology
Time-Lapse Imaging
Journal
Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
30
04
2018
accepted:
04
12
2018
pubmed:
16
1
2019
medline:
7
5
2019
entrez:
16
1
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30643265
doi: 10.1038/s41590-018-0293-x
pii: 10.1038/s41590-018-0293-x
pmc: PMC6402828
mid: NIHMS1515780
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
ELMO1 protein, human
0
ELMO1 protein, mouse
0
Leukotriene B4
1HGW4DR56D
Complement C5a
80295-54-1
Collagen
9007-34-5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
141-151Subventions
Organisme : NIMH NIH HHS
ID : R01 MH096484
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007496
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS101281
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI114554
Pays : United States
Organisme : Wellcome Trust
ID : 206566/Z/17/Z
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R35 GM122542
Pays : United States
Organisme : NHLBI NIH HHS
ID : F30 HL126385
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009109
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL120840
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS083542
Pays : United States
Commentaires et corrections
Type : CommentIn
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