| Title |
The caspase-8/RIPK3 signaling axis in antigen presenting cells controls the inflammatory arthritic response
|
|---|---|
| Published in |
Arthritis Research & Therapy, October 2017
|
| DOI | 10.1186/s13075-017-1436-4 |
| Pubmed ID | |
| Authors |
Salina Dominguez, Anna B. Montgomery, G. Kenneth Haines, Christina L. Bloomfield, Carla M. Cuda |
| Abstract |
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. 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. 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. 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. |
X Demographics
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 32 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 32 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Doctoral Student | 8 | 25% |
| Student > Ph. D. Student | 6 | 19% |
| Researcher | 3 | 9% |
| Student > Bachelor | 2 | 6% |
| Student > Master | 2 | 6% |
| Other | 4 | 13% |
| Unknown | 7 | 22% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 12 | 38% |
| Medicine and Dentistry | 7 | 22% |
| Agricultural and Biological Sciences | 4 | 13% |
| Immunology and Microbiology | 1 | 3% |
| Neuroscience | 1 | 3% |
| Other | 0 | 0% |
| Unknown | 7 | 22% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 06 October 2017.
All research outputs
#22,764,772
of 25,382,440 outputs
Outputs from Arthritis Research & Therapy
#3,132
of 3,380 outputs
Outputs of similar age
#290,905
of 331,155 outputs
Outputs of similar age from Arthritis Research & Therapy
#44
of 48 outputs
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