The caspase-8/RIPK3 signaling axis in antigen presenting cells controls the inflammatory arthritic response.
The caspase-8/RIPK3 signaling axis in antigen presenting cells controls the inflammatory arthritic response.
复制标题
DOI：
10.1186/s13075-017-1436-4
复制
发表时间：
2017-10-04
影响因子：
4.9
通讯作者：
Cuda CM
中科院分区：
文献类型：
--
作者：
Dominguez S;Montgomery AB;Haines GK 3rd;Bloomfield CL;Cuda CM
半胱天冬酶-8是细胞凋亡的启动子和坏死性凋亡的抑制子，但在细胞死亡之外维持涉及抑制受体相互作用的丝氨酸-苏氨酸激酶（RIPKs）的功能。一项全基因组关联研究荟萃分析显示，在含有编码半胱氨酸蛋白酶-8的基因的基因座内，存在一个与类风湿性关节炎（RA）发生风险相关的SNP。先天性免疫细胞，如巨噬细胞和树突状细胞，作为自身免疫性疾病发病机制的促进者，特别是RA，正在获得动力。因此，我们研究了这些抗原呈递细胞群中caspase-8在类似于RA效应阶段的关节炎模型发病机制中的参与。 Cre LysM Casp 8 flox/flox和Cre CD 11 c Casp 8 flox/flox小鼠通过Casp 8 flox/flox和Cre LysM或Cre CD 11 c小鼠之间的杂交来繁殖。产生RIPK 3-/- Cre LysM Casp 8 flox/flox和RIPK 3-/- Cre CD 11 c Casp 8 flox/flox小鼠以评估RIPK 3贡献。小鼠经受K/BxN血清转移诱导的关节炎。使用基于Luminex的测定来测量细胞因子/趋化因子。组织学分析用于检查关节损伤。产生混合骨髓嵌合体以评估滑膜细胞存活。采用流式细胞术分析来表征细胞分布。对于关节炎，使用重复测量的双因素方差分析（ANOVA）评估组间差异。所有其他数据通过Mann-Whitney检验进行比较。我们发现，完整的caspase-8信号在关节中的溶菌酶-M和CD 11 c表达细胞中保持相反的作用;即，caspase-8在CD 11 c表达细胞中对延迟关节炎诱导至关重要，而溶菌酶M表达细胞中的caspase-8阻碍关节炎的解决。半胱天冬酶-8也参与维持滑膜组织驻留的巨噬细胞，这可以限制关节炎。在两种半胱天冬酶-8缺失构建体中RIPK 3的整体缺失导致对关节炎的反应通过可能独立于细胞死亡的机制恢复到对照水平。混合骨髓嵌合小鼠证明，caspase-8缺陷并不赋予滑膜巨噬细胞和树突状细胞群体的优先扩增，caspase-8缺陷的滑膜群体也不屈服于RIPK 3介导的坏死性死亡。这些数据表明，caspase-8在滑膜抗原呈递细胞中的功能是通过控制RIPK 3的作用来调节对炎症刺激的反应，这种微妙的平衡维持了关节内的稳态。本文的在线版本（doi：10.1186/s13075-017-1436-4）包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1186/s13075-017-1436-4) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
27.4
作者：
Chamberlain ND;Kim SJ;Vila OM;Volin MV;Volkov S;Pope RM;Arami S;Mandelin AM 2nd;Shahrara S
通讯作者：
Shahrara S
影响因子：
4.4
作者：
Corr, M;Crain, B
通讯作者：
Crain, B
影响因子：
32.4
作者：
Kang, Tae-Bong;Yang, Seung-Hoon;Wallach, David
通讯作者：
Wallach, David
影响因子：
4.9
作者：
Choulaki C;Papadaki G;Repa A;Kampouraki E;Kambas K;Ritis K;Bertsias G;Boumpas DT;Sidiropoulos P
通讯作者：
Sidiropoulos P
影响因子：
4.4
作者：
Beisner, DR;Ch'en, IL;Hedrick, SM
通讯作者：
Hedrick, SM