Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda, Chiba 278-0022, Japan.
Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki 2669, Noda, Chiba 278-0022, Japan; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhong Shan Er Lu, Guangzhou, Guangdong Province 510080, China.
Cell Rep. 2022 Aug 2;40(5):111158. doi: 10.1016/j.celrep.2022.111158.
Dendritic cell immunoreceptor (DCIR; Clec4a2), a member of the C-type lectin receptor family, plays important roles in homeostasis of the immune and bone systems. However, the intestinal role of this molecule is unclear. Here, we show that dextran sodium sulfate (DSS)-induced colitis and azoxymethane-DSS-induced intestinal tumors are reduced in Clec4a2 mice independently of intestinal microbiota. STAT5 phosphorylation and expression of Csf2 and tight junction genes are enhanced, while Il17a and Cxcl2 are suppressed in the Clec4a2 mouse colon, which exhibits reduced infiltration of neutrophils and myeloid-derived suppressor cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) administration ameliorates DSS colitis associated with reduced Il17a and enhanced tight junction gene expression, whereas anti-GM-CSF exacerbates symptoms. Furthermore, anti-NA2, a ligand for DCIR, ameliorates colitis and prevents colorectal tumors. These observations indicate that blocking DCIR signaling ameliorates colitis and suppresses colonic tumors, suggesting DCIR as a possible target for the treatment of these diseases.
树突状细胞免疫受体（DCIR；Clec4a2）是 C 型凝集素受体家族的成员，在免疫和骨骼系统的稳态中发挥重要作用。然而，该分子在肠道中的作用尚不清楚。在这里，我们发现 DCIR 缺失的小鼠在不依赖于肠道菌群的情况下，葡聚糖硫酸钠（DSS）诱导的结肠炎和氧化偶氮甲烷-DSS 诱导的肠道肿瘤的发生减少。STAT5 磷酸化和 CSF2 及紧密连接基因的表达增强，而 Clec4a2 小鼠结肠中的 Il17a 和 Cxcl2 受到抑制，其中性粒细胞和髓系来源的抑制细胞浸润减少。粒细胞-巨噬细胞集落刺激因子（GM-CSF）的给药可改善与 Il17a 减少和紧密连接基因表达增强相关的 DSS 结肠炎，而抗 GM-CSF 则加重症状。此外，抗 NA2，一种 DCIR 的配体，可改善结肠炎并预防结直肠肿瘤。这些观察结果表明，阻断 DCIR 信号可改善结肠炎并抑制结肠肿瘤，提示 DCIR 可能是治疗这些疾病的一个潜在靶点。
