We have previously reported using gene-deficient mice that the interleukin (IL)-23p19 subunit is required for the development of innate immune-driven arthritic pain and disease. We aimed to explore here, using a number of in vivo approaches, how the IL-23p19 subunit can mechanistically control arthritic pain and disease in a T- and B- lymphocyte-independent manner. 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. 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. The data presented should aid IL-23 targeting both in the choice of inflammatory disease to be treated and the design of clinical trials.

中文翻译：

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IL-23在实验性炎症性关节炎疼痛和疾病中的作用模式


我们之前曾使用基因缺陷小鼠报道过，白细胞介素 (IL)-23p19 亚基是先天免疫驱动的关节炎疼痛和疾病的发展所必需的。我们的目的是使用多种体内方法探索 IL-23p19 亚基如何以不依赖于 T 淋巴细胞和 B 淋巴细胞的方式机械地控制关节炎疼痛和疾病。我们在野生型和 Il23p19−/− 小鼠中使用酵母聚糖诱导的关节炎 (ZIA) 模型，通过辐射嵌合体方法以及单细胞 RNAseq 和 qPCR 分析，来鉴定表达 IL23p19 和 IL-23 反应的细胞发炎关节的类型。该模型还用于研究中和单克隆抗体 (mAb) 阻断 IL-23p19 亚基的功效。建立了一种新型 IL-23 驱动的关节炎模型，可以鉴定 IL-23 控制疼痛和疾病的假定下游介质。疼痛和关节炎分别通过相对静态重量分布和组织学进行评估。我们提供的证据表明 (i) IL-23p19+ 非骨髓源性巨噬细胞是 ZIA 疼痛和疾病的发生所必需的，(ii) IL-23p19 亚基的预防性和治疗性阻断可改善 ZIA 疼痛和疾病，以及 (iii)全身施用 IL-23 可以以依赖于 TNF、GM-CSF、CCL17 和环氧合酶活性的方式诱发关节炎疼痛和疾病，但与淋巴细胞、CGRP、NGF 和 P 物质无关。所提供的数据应有助于 IL-23 靶向要治疗的炎症性疾病的选择和临床试验的设计。