Abstract
BackgroundCaspase-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.MethodsCreLysMCasp8flox/flox and CreCD11cCasp8flox/flox mice were bred via a cross between Casp8flox/flox and CreLysM or CreCD11c mice. RIPK3–/–CreLysMCasp8flox/flox and RIPK3–/–CreCD11cCasp8flox/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.ResultsWe 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.ConclusionsThese 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.
Highlights
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)
CreLysMCasp8flox/flox mice display accelerated resolution, while CreCD11cCasp8flox/flox mice exhibit accelerated initiation, of K/BxN serum-transfer-induced arthritis Since we have previously published that caspase-8 signaling in myeloid cells and dendritic cells (DCs) is critical to suppress systemic inflammation and caspase-8 has been linked to Rheumatoid arthritis (RA) susceptibility, the role that cell-specific caspase-8 plays in the development of acute inflammation in young mice prior to overt development of autoimmune disease was evaluated using the K/BxN serum-transferinduced arthritis model
CreLysMCasp8flox/flox mice presented with an accelerated resolution and reduced severity of K/BxN serum-transfer-induced arthritis compared to Casp8flox/flox mice beginning at day 7 following injection (Fig. 1a)
Summary
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). DCs contribute to the marked increase in leukocyte infiltration into the synovial tissue in patients with RA [10], where they may contribute to the initiation of disease by producing cytokines and presenting arthritogenic antigens, which in combination activate autoreactive T cells [11, 12]. Lower levels of circulating DCs in patients with RA suggest that plasmacytoid and myeloid DCs may selectively home to the inflamed joint [18,19,20,21,22] This decrease correlates with the presence of a population of DCs enriched for a high T cell stimulatory capacity in the inflamed synovium [18,19,20,21,22]. Macrophages and DCs are clearly implicated in the pathogenesis of RA, relatively little is known about the mechanisms behind their involvement
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