In addition to their well characterized role in mediating IgE-dependent allergic diseases, aberrant accumulation and activation of mast cells (MCs) is associated with many non-allergic inflammatory diseases, whereby their activation is likely triggered by non-IgE stimuli (e.g., IL-33). Siglec-8 is an inhibitory receptor expressed on MCs and eosinophils that has been shown to inhibit IgE-mediated MC responses and reduce allergic inflammation upon ligation with a monoclonal antibody (mAb). Herein, we evaluated the effects of an anti-Siglec-8 mAb (anti-S8) in non-allergic disease models of experimental cigarette-smoke-induced chronic obstructive pulmonary disease and bleomycin-induced lung injury in Siglec-8 transgenic mice. Therapeutic treatment with anti-S8 inhibited MC activation and reduced recruitment of immune cells, airway inflammation, and lung fibrosis. Similarly, using a model of MC-dependent, IL-33-induced inflammation, anti-S8 treatment suppressed neutrophil influx, and cytokine production through MC inhibition. Transcriptomic profiling of MCs further demonstrated anti-S8-mediated downregulation of MC signaling pathways induced by IL-33, including TNF signaling via NF-κB. Collectively, these findings demonstrate that ligating Siglec-8 with an antibody reduces non-allergic inflammation and inhibits IgE-independent MC activation, supporting the evaluation of an anti-Siglec-8 mAb as a therapeutic approach in both allergic and non-allergic inflammatory diseases in which MCs play a role.

除了它们在介导 IgE 依赖性过敏性疾病中的明确作用外，肥大细胞 (MC) 的异常积累和激活与许多非过敏性炎症性疾病有关，因此它们的激活可能由非 IgE 刺激物（例如，IL -33). Siglec-8 是一种在 MC 和嗜酸性粒细胞上表达的抑制性受体，已显示可抑制 IgE 介导的 MC 反应，并在与单克隆抗体 (mAb) 连接后减少过敏性炎症。在此，我们评估了抗 Siglec-8 单克隆抗体（抗 S8）在 Siglec-8 转基因小鼠的实验性香烟烟雾诱导的慢性阻塞性肺病和博来霉素诱导的肺损伤的非过敏性疾病模型中的作用。抗 S8 治疗可抑制 MC 活化并减少免疫细胞的募集、气道炎症、和肺纤维化。同样，使用 MC 依赖性、IL-33 诱导的炎症模型，抗 S8 治疗通过 MC 抑制抑制中性粒细胞流入和细胞因子产生。MC 的转录组学分析进一步证明了抗 S8 介导的 IL-33 诱导的 MC 信号通路下调，包括通过 NF-κB 的 TNF 信号通路。总的来说，这些发现表明，将 Siglec-8 与抗体结合可减少非过敏性炎症并抑制 IgE 非依赖性 MC 激活，支持评估抗 Siglec-8 mAb 作为过敏性和非过敏性炎症疾病的治疗方法MC 在其中发挥作用。MC 的转录组学分析进一步证明了抗 S8 介导的 IL-33 诱导的 MC 信号通路下调，包括通过 NF-κB 的 TNF 信号通路。总的来说，这些发现表明，将 Siglec-8 与抗体结合可减少非过敏性炎症并抑制 IgE 非依赖性 MC 激活，支持评估抗 Siglec-8 mAb 作为过敏性和非过敏性炎症疾病的治疗方法MC 在其中发挥作用。MC 的转录组学分析进一步证明了抗 S8 介导的 IL-33 诱导的 MC 信号通路下调，包括通过 NF-κB 的 TNF 信号通路。总的来说，这些发现表明，将 Siglec-8 与抗体结合可减少非过敏性炎症并抑制 IgE 非依赖性 MC 激活，支持评估抗 Siglec-8 mAb 作为过敏性和非过敏性炎症疾病的治疗方法MC 在其中发挥作用。