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IFN‐γ‐dependent nitric oxide suppresses Brucella ‐induced arthritis by inhibition of inflammasome activation
Author(s) -
Lacey Carolyn A.,
Chambers Catherine A.,
Mitchell William J.,
Skyberg Jerod A.
Publication year - 2019
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.4mia1018-409r
Subject(s) - nitric oxide , biology , inflammasome , brucella abortus , arthritis , brucella , microbiology and biotechnology , immunology , dose dependence , brucellosis , pharmacology , inflammation , endocrinology
Brucellosis, caused by the intracellular bacterial pathogen Brucella , is a globally important zoonotic disease for which arthritis is the most common focal complication in humans. Wild‐type mice infected systemically with Brucella typically do not exhibit arthritis, but mice lacking IFN‐γ develop arthritis regardless of the route of Brucella infection. Here, we investigated mechanisms by which IFN‐γ suppresses Brucella ‐induced arthritis. Several cell types, including innate lymphoid cells, contributed to IFN‐γ production and suppression of joint swelling. IFN‐γ deficiency resulted in elevated joint IL‐1β levels, and severe joint inflammation that was entirely inflammasome dependent, and in particular, reliant on the NLRP3 inflammasome. IFN‐γ was vital for induction of the nitric oxide producing enzyme, iNOS, in infected joints, and nitric oxide directly inhibited IL‐1β production and inflammasome activation in Brucella ‐infected macrophages in vitro. During in vivo infection, iNOS deficiency resulted in an increase in IL‐1β and inflammation in Brucella ‐infected joints. Collectively, this data indicate that IFN‐γ prevents arthritis both by limiting Brucella infection, and by inhibiting excessive inflammasome activation through the induction of nitric oxide.