Ishikawa Chie, Saito Ryo, Suehiro Masataka, Ishii Kaori, Yanase Yuhki, Kawaguchi Tomoko, Uchida Kazue, Yanagida Nozomi, Numata Tomofumi, Sasaki Wataru, Kamigaki Rina, Takeno Sachio, Tanaka Akio
Department of Dermatology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Department of Otorhinolaryngology, Head and Neck Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Front Immunol. 2025 Jul 3;16:1571120. doi: 10.3389/fimmu.2025.1571120. eCollection 2025.
Oncostatin M (OSM) is a cytokine that mediates inflammatory processes and is overexpressed in skin lesions of atopic dermatitis (AD). By amplifying neural responses to chemicals such as histamine, OSM increases sensitivity to pruritus. However, the morphological effects of OSM on peripheral sensory nerves and their subsequent impact on pruritus remain unclear. This study investigated OSM-induced peripheral nerve elongation, which may contribute to skin hypersensitivity.
We assessed neurite outgrowth using primary mouse dorsal root ganglion (DRG) cells treated with OSM, IL-31, or nerve growth factor. Next, we pre-treated the cells with inhibitors of downstream signaling pathways of OSM, including extracellular signal-regulated kinase (ERK), signal transducers and activator of transcription (STAT) 3, c-Jun N-terminal kinase (JNK), and p38, followed by OSM administration to measure neurite outgrowth. Furthermore, OSM receptor β-overexpressing cell lines were established by gene transfer into the DRG cell line, and nerve elongation was measured after OSM administration. studies involved OSM administration in mouse skin models. Immunofluorescence staining was used to evaluate nerve elongation. We examined whether OSM-infused mice had increased hypersensitivity to mechanical stimuli-induced pruritus. Various cytokine stimuli were applied to CD4+ T cells isolated from healthy humans to examine the conditions under which OSM production increases.
OSM significantly induced neurite outgrowth in DRG cells and the effect of OSM surpassed the effects of IL-31 and nerve growth factor. The neurite outgrowth effect of OSM involved the JAK/STAT3, MEK/ERK, and p38/MAPK pathways. Compared to control cells, DRG cell lines that overexpressed OSM receptor β showed significantly enhanced neurite outgrowth upon OSM treatment. , OSM treatment increased nerve elongation in the mouse dermis. Behavioral assays in mice showed that OSM administration increased sensitivity to mechanical stimuli. IL-4 and TNFα increased OSM production in CD4+ T cells.
OSM induces neurite elongation and may contribute to skin hypersensitivity. This suggests the potential utilization of OSM as a therapeutic target for inflammatory skin diseases such as AD.
抑瘤素M（OSM）是一种介导炎症过程的细胞因子，在特应性皮炎（AD）的皮肤病变中过表达。通过放大对组胺等化学物质的神经反应，OSM增加了对瘙痒的敏感性。然而，OSM对周围感觉神经的形态学影响及其随后对瘙痒的影响仍不清楚。本研究调查了OSM诱导的周围神经伸长，这可能导致皮肤超敏反应。
我们使用经OSM、IL-31或神经生长因子处理的原代小鼠背根神经节（DRG）细胞评估神经突生长。接下来，我们用OSM下游信号通路的抑制剂预处理细胞，包括细胞外信号调节激酶（ERK）、信号转导和转录激活因子（STAT）3、c-Jun氨基末端激酶（JNK）和p38，然后给予OSM以测量神经突生长。此外，通过基因转移到DRG细胞系中建立过表达OSM受体β的细胞系，并在给予OSM后测量神经伸长。研究涉及在小鼠皮肤模型中给予OSM。免疫荧光染色用于评估神经伸长。我们检查了注入OSM的小鼠对机械刺激诱导的瘙痒是否增加了超敏反应。将各种细胞因子刺激应用于从健康人分离的CD4+T细胞，以检查OSM产生增加的条件。
OSM显著诱导DRG细胞中的神经突生长，且OSM的作用超过了IL-31和神经生长因子。OSM的神经突生长作用涉及JAK/STAT3、MEK/ERK和p38/MAPK途径。与对照细胞相比，过表达OSM受体β的DRG细胞系在OSM处理后显示出显著增强的神经突生长。此外，OSM处理增加了小鼠真皮中的神经伸长。小鼠的行为分析表明，给予OSM增加了对机械刺激的敏感性。IL-4和TNFα增加了CD4+T细胞中OSM的产生。
OSM诱导神经突伸长，并可能导致皮肤超敏反应。这表明OSM作为AD等炎症性皮肤病的治疗靶点具有潜在的应用价值。
