METHODS: We used the zymosan-induced arthritis (ZIA) model in wild-type and Il23p19-/- mice, by a radiation chimera approach, and by single cell RNAseq and qPCR analyses, to identify the IL23p19-expressing and IL-23-responding cell type(s) in the inflamed joints. This model was also utilized to investigate the efficacy of IL-23p19 subunit blockade with a neutralizing monoclonal antibody (mAb). A novel IL-23-driven arthritis model was established, allowing the identification of putative downstream mediators of IL-23 in the control of pain and disease. Pain and arthritis were assessed by relative static weight distribution and histology, respectively.
RESULTS: We present evidence that (i) IL-23p19+ non-bone marrow-derived macrophages are required for the development of ZIA pain and disease, (ii) prophylactic and therapeutic blockade of the IL-23p19 subunit ameliorate ZIA pain and disease and (iii) systemically administered IL-23 can induce arthritic pain and disease in a manner dependent on TNF, GM-CSF, CCL17 and cyclooxygenase activity, but independently of lymphocytes, CGRP, NGF and substance P.
CONCLUSIONS: The data presented should aid IL-23 targeting both in the choice of inflammatory disease to be treated and the design of clinical trials.
方法:我们在野生型和Il23p19-/-小鼠中使用了酵母聚糖诱导的关节炎(ZIA)模型,通过辐射嵌合体方法,并通过单细胞RNAseq和qPCR分析,以鉴定发炎关节中表达IL23p19和响应IL-23的细胞类型。该模型还用于研究用中和单克隆抗体(mAb)阻断IL-23p19亚基的功效。建立了一种新的IL-23驱动的关节炎模型,允许鉴定IL-23在控制疼痛和疾病中的推定下游介质。疼痛和关节炎通过相对静态体重分布和组织学评估,分别。
结果:我们提供的证据表明(i)IL-23p19+非骨髓来源的巨噬细胞是ZIA疼痛和疾病发展所必需的,(ii)预防性和治疗性阻断IL-23p19亚基改善ZIA疼痛和疾病,和(iii)全身给药IL-23可以以依赖于TNF的方式诱导关节炎疼痛和疾病,GM-CSF,CCL17和环氧合酶活性,但与淋巴细胞无关,CGRP,NGF和P物质。
结论:所提供的数据应有助于IL-23靶向治疗的炎症性疾病的选择和临床试验的设计。