Medical Research Council, Laboratory of Molecular Biology, Cambridge, Cambridgeshire, CB2 0QH, UK.
The Francis Crick Institute, London, NW1 1AT, UK.
Mucosal Immunol. 2021 Jan;14(1):26-37. doi: 10.1038/s41385-020-0298-2. Epub 2020 May 26.
Type-2 immunity is characterised by interleukin (IL)-4, IL-5 and IL-13, eosinophilia, mucus production, IgE, and alternatively activated macrophages (AAM). However, despite the lack of neutrophil chemoattractants such as CXCL1, neutrophils, a feature of type-1 immunity, are observed in type-2 responses. Consequently, alternative mechanisms must exist to ensure that neutrophils can contribute to type-2 immune reactions without escalation of deleterious inflammation. We now demonstrate that type-2 immune-associated neutrophil infiltration is regulated by the mouse RNase A homologue, eosinophil-associated ribonuclease 11 (Ear11), which is secreted by AAM downstream of IL-25-stimulated ILC2. Transgenic overexpression of Ear11 resulted in tissue neutrophilia, whereas Ear11-deficient mice have fewer resting tissue neutrophils, whilst other type-2 immune responses are not impaired. Notably, administration of recombinant mouse Ear11 increases neutrophil motility and recruitment. Thus, Ear11 helps maintain tissue neutrophils at homoeostasis and during type-2 reactions when chemokine-producing classically activated macrophages are infrequently elicited.
2 型免疫的特征是白细胞介素 (IL)-4、IL-5 和 IL-13、嗜酸性粒细胞增多、黏液产生、IgE 和选择性激活的巨噬细胞 (AAM)。然而，尽管缺乏中性粒细胞趋化因子，如 CXCL1，但在 2 型反应中也观察到 1 型免疫的特征性中性粒细胞。因此，必须存在替代机制来确保中性粒细胞能够促进 2 型免疫反应，而不会加剧有害炎症。我们现在证明，2 型免疫相关的中性粒细胞浸润受小鼠核糖核酸酶 A 同源物、嗜酸性粒细胞相关核糖核酸酶 11（Ear11）调节，AAM 在 IL-25 刺激的 ILC2 下游分泌 Ear11。Ear11 的转基因过表达导致组织中性粒细胞增多，而 Ear11 缺陷小鼠的静止组织中性粒细胞较少，而其他 2 型免疫反应不受损害。值得注意的是，重组小鼠 Ear11 的给药增加了中性粒细胞的迁移和募集。因此，Ear11 有助于在组织中性粒细胞稳态和 2 型反应期间维持组织中性粒细胞，此时很少引发产生趋化因子的经典激活的巨噬细胞。
