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The caspase-8/RIPK3 signaling axis in antigen presenting cells controls the inflammatory arthritic response.
Dominguez, Salina; Montgomery, Anna B; Haines, G Kenneth; Bloomfield, Christina L; Cuda, Carla M.
Affiliation
  • Dominguez S; Department of Medicine, Division of Rheumatology, Northwestern University, Feinberg School of Medicine, 240 East Huron Street, M300, Chicago, IL, 60611, USA.
  • Montgomery AB; Department of Medicine, Division of Rheumatology, Northwestern University, Feinberg School of Medicine, 240 East Huron Street, M300, Chicago, IL, 60611, USA.
  • Haines GK; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • Bloomfield CL; Department of Medicine, Division of Rheumatology, Northwestern University, Feinberg School of Medicine, 240 East Huron Street, M300, Chicago, IL, 60611, USA.
  • Cuda CM; Department of Medicine, Division of Rheumatology, Northwestern University, Feinberg School of Medicine, 240 East Huron Street, M300, Chicago, IL, 60611, USA. c-cuda@northwestern.edu.
Arthritis Res Ther ; 19(1): 224, 2017 Oct 04.
Article in En | MEDLINE | ID: mdl-28978351
ABSTRACT

BACKGROUND:

Caspase-8 is a well-established initiator of apoptosis and suppressor of necroptosis, but maintains functions beyond cell death that involve suppression of receptor-interacting serine-threonine kinases (RIPKs). A genome-wide association study meta-analysis revealed an SNP associated with risk of rheumatoid arthritis (RA) development within the locus containing the gene encoding for caspase-8. Innate immune cells, like macrophages and dendritic cells, are gaining momentum as facilitators of autoimmune disease pathogenesis, and, in particular, RA. Therefore, we examined the involvement of caspase-8 within these antigen-presenting cell populations in the pathogenesis of an arthritis model that resembles the RA effector phase.

METHODS:

Cre LysM Casp8 flox/flox and Cre CD11c Casp8 flox/flox mice were bred via a cross between Casp8 flox/flox and Cre LysM or Cre CD11c mice. RIPK3 -/- Cre LysM Casp8 flox/flox and RIPK3 -/- Cre CD11c Casp8 flox/flox mice were generated to assess RIPK3 contribution. Mice were subjected to K/BxN serum-transfer-induced arthritis. Luminex-based assays were used to measure cytokines/chemokines. Histological analyses were utilized to examine joint damage. Mixed bone marrow chimeras were generated to assess synovial cell survival. Flow cytometric analysis was employed to characterize cellular distribution. For arthritis, differences between the groups were assessed using two-way analysis of variance (ANOVA) for repeated measurements. All other data were compared by the Mann-Whitney test.

RESULTS:

We show that intact caspase-8 signaling maintains opposing roles in lysozyme-M- and CD11c-expressing cells in the joint; namely, caspase-8 is crucial in CD11c-expressing cells to delay arthritis induction, while caspase-8 in lysozyme M-expressing cells hinders arthritis resolution. Caspase-8 is also implicated in the maintenance of synovial tissue-resident macrophages that can limit arthritis. Global loss of RIPK3 in both caspase-8 deletion constructs causes the response to arthritis to revert back to control levels via a mechanism potentially independent of cell death. Mixed bone marrow chimeric mice demonstrate that caspase-8 deficiency does not confer preferential expansion of synovial macrophage and dendritic cell populations, nor do caspase-8-deficient synovial populations succumb to RIPK3-mediated necroptotic death.

CONCLUSIONS:

These data demonstrate that caspase-8 functions in synovial antigen-presenting cells to regulate the response to inflammatory stimuli by controlling RIPK3 action, and this delicate balance maintains homeostasis within the joint.
Subject(s)
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Arthritis, Experimental / Arthritis, Rheumatoid / Caspase 8 / Receptor-Interacting Protein Serine-Threonine Kinases Limits: Animals Language: En Journal: Arthritis Res Ther Journal subject: REUMATOLOGIA Year: 2017 Document type: Article Affiliation country:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Arthritis, Experimental / Arthritis, Rheumatoid / Caspase 8 / Receptor-Interacting Protein Serine-Threonine Kinases Limits: Animals Language: En Journal: Arthritis Res Ther Journal subject: REUMATOLOGIA Year: 2017 Document type: Article Affiliation country: