Session Type: ACR Concurrent Abstract Session
Session Time: 9:00AM-10:30AM
Background/Purpose: Rheumatoid arthritis (RA) manifests in persistent synovial inflammation, cellular infiltration and pro-inflammatory cytokine production, and results in progressive joint destruction. Dendritic cells (DCs) have been implicated in RA progression and persistence through either antigen presentation to autoreactive T cells or differentiation into synoviocytes, yet the mechanisms underlying these activities are not fully elucidated. We identified that caspase 8, an enzyme that initiates apoptosis and suppresses necroptosis by inhibition of RIPK1/3 signaling in a multitude of cells, is a novel DC-specific inhibitor of inflammatory processes independent of its known role in cell survival. Further, a genome-wide association study identified an RA risk single nucleotide polymorphism within the locus that contains the gene encoding for caspase 8. However, the impact of DC-specific loss of caspase 8 on arthritis progression has yet to be examined.
Methods: Mice with caspase 8 flanked by loxP sites (Casp8fl/fl, WT) were bred to mice expressing Cre under control of the CD11c gene promoter (CreCD11c) to generate CreCD11cCasp8fl/fl mice. CreCD11cCasp8fl/fl mice were crossed with RIPK3-/- mice to determine the involvement of this signaling partner. The K/BxN serum-transfer model of arthritis was utilized and clinical severity was assessed. Ankle sections were stained with H&E and scored by a pathologist blinded to the study to assess pathology. Flow cytometric analysis was used to characterize naïve and arthritic joints.
Results: CreCD11cCasp8fl/fl mice showed accelerated initiation of arthritis, as evidenced by increased changes in ankle width and clinical scores on day 2 and 4, as well as increased joint damage compared to WT. DC-specific deletion of caspase 8 affects not only synovial DCs but also synovial macrophage populations in both the naïve and arthritic joint. CreCD11cCasp8fl/fl synovial DCs show elevated expression of costimulatory molecule CD86 compared to WT. Further, we previously demonstrated that naïve mouse joints contain MHC II+ and MHC II– macrophages, the majority being MHC II– tissue-resident macrophages that can limit arthritis initiation, and CreCD11cCasp8fl/fl joints exhibit a reduced proportion of these disease limiting tissue-resident macrophages compared to WT. CreCD11cCasp8fl/fl MHC II+ and MHC II– macrophage populations express reduced CD36, a scavenger receptor for oxidized low-density lipoprotein and apoptotic neutrophils, and CD206, a protein active in endocytosis/phagocytosis, compared to WT. Strikingly, these alterations are a function of overactive RIPK3 signaling, as knockout of RIPK3 in CreCD11cCasp8fl/fl mice is sufficient to reverse all effects of caspase 8 deletion on joint homeostasis under steady-state and arthritic conditions.
Conclusion: The caspase 8/RIPK3 signaling axis in the joint plays a vital role in controlling arthritis pathogenesis, as global knockout of RIPK3 prevents the pathogenic phenotypes within the joint initiated by DC-specific caspase 8-deletion. These data have implications for RA by elucidating previously unknown cell-specific functions of a potentially useful target for therapy.
To cite this abstract in AMA style:Dominguez S, Perlman HR, Cuda C. The Caspase 8/RIPK3 Signaling Axis in Dendritic Cells Controls Joint Homeostasis Under Steady-State and Arthritic Conditions [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/the-caspase-8ripk3-signaling-axis-in-dendritic-cells-controls-joint-homeostasis-under-steady-state-and-arthritic-conditions/. Accessed December 1, 2020.
« Back to 2016 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-caspase-8ripk3-signaling-axis-in-dendritic-cells-controls-joint-homeostasis-under-steady-state-and-arthritic-conditions/