Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia.
Janssen Research & Development, San Diego, CA, USA.
Arthritis Res Ther. 2024 Aug 6;26(1):148. doi: 10.1186/s13075-024-03380-z.
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.
我们之前曾报道过，白细胞介素（IL）-23p19 亚基对于先天免疫驱动的关节炎性疼痛和疾病的发展是必需的。在这里，我们旨在通过多种体内方法来探索 IL-23p19 亚基如何在不依赖 T 和 B 淋巴细胞的情况下从机制上控制关节炎性疼痛和疾病。
我们使用酵母聚糖诱导的关节炎（ZIA）模型，在野生型和 Il23p19 小鼠中，通过辐射嵌合体方法，以及单细胞 RNAseq 和 qPCR 分析，来鉴定在炎症关节中表达 IL23p19 和对 IL-23 有反应的细胞类型。该模型还用于研究中和单克隆抗体（mAb）阻断 IL-23p19 亚基的疗效。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潜在下游介质。通过相对静态体重分布和组织学分别评估疼痛和关节炎。
我们提出的证据表明：（i）IL-23p19 非骨髓来源的巨噬细胞对于 ZIA 疼痛和疾病的发展是必需的；（ii）预防性和治疗性阻断 IL-23p19 亚基可改善 ZIA 疼痛和疾病；（iii）系统给予 IL-23 可诱导依赖 TNF、GM-CSF、CCL17 和环氧化酶活性的关节炎性疼痛和疾病，但不依赖于淋巴细胞、CGRP、NGF 和 P 物质。
所呈现的数据应有助于针对 IL-23 的靶向治疗，包括选择要治疗的炎症性疾病和临床试验的设计。
