Neutrophil-derived leukotriene B4 is required for inflammatory arthritis.
Neutrophils serve as a vanguard of the acute innate immune response to invading pathogens. Neutrophils are also abundant at sites of autoimmune inflammation, such as the rheumatoid joint, although their pathophysiologic role is incompletely defined and relevant effector functions remain obscure. Using genetic and pharmacologic approaches in the K/BxN serum transfer model of arthritis, we find that autoantibody-driven erosive synovitis is critically reliant on the generation of leukotrienes, and more specifically on leukotriene B4 (LTB4), for disease induction as well as perpetuation. Pursuing the cellular source for this mediator, we find via reconstitution experiments that mast cells are a dispensable source of leukotrienes, whereas arthritis susceptibility can be restored to leukotriene-deficient mice by intravenous administration of wild-type neutrophils. These experiments demonstrate a nonredundant role for LTB4 in inflammatory arthritis and define a neutrophil mediator involved in orchestrating the synovial eruption.
Chen
Mei
M
Department of Medicine and Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Lam
Bing K
BK
Kanaoka
Yoshihide
Y
Nigrovic
Peter A
PA
Audoly
Laurent P
LP
Austen
K Frank
KF
Lee
David M
DM
D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*
D007975:Leukotriene B4