Unidad de Regulación Génica, Unidad Funcional de Investigación en Enfermedades Crónicas, Instituto de Salud Carlos III, Carretera Majadahonda-Pozuelo Km2, 28220 Madrid, Spain.
Unidad de Innovación Biomédica, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Avenida Complutense, 40, 28040 Madrid, Spain.
Int J Mol Sci. 2022 Mar 15;23(6):3171. doi: 10.3390/ijms23063171.
The Hedgehog (Hh) pathway is essential for the embryonic development and homeostatic maintenance of many adult tissues and organs. It has also been associated with some functions of the innate and adaptive immune system. However, its involvement in the immune response has not been well determined. Here we study the role of Hh signalling in the modulation of the immune response by using the Ptch-1-LacZ mouse model (hereinafter referred to as ), in which the hemizygous inactivation of Patched-1, the Hh receptor gene, causes the constitutive activation of Hh response genes. The in vitro TCR stimulation of spleen and lymph node (LN) T cells showed increased levels of Th2 cytokines (IL-4 and IL-10) in cells compared to control cells from wild-type (wt) littermates, suggesting that the Th2 phenotype is favoured by Hh pathway activation. In addition, CD4 cells secreted less IL-17, and the establishment of the Th1 phenotype was impaired in mice. Consistently, in response to an inflammatory challenge by the induction of experimental autoimmune encephalomyelitis (EAE), mice showed milder clinical scores and more minor spinal cord damage than wt mice. These results demonstrate a role for the Hh/ptch pathway in immune response modulation and highlight the usefulness of the mouse model for the study of T-cell-mediated diseases and for the search for new therapeutic strategies in inflammatory diseases.
Hedgehog (Hh) 信号通路对于许多成年组织和器官的胚胎发育和体内平衡维持至关重要。它还与先天和适应性免疫系统的一些功能有关。然而，其在免疫反应中的作用尚未得到很好的确定。在这里，我们使用 Ptch-1-LacZ 小鼠模型（以下简称 ）研究了 Hh 信号在免疫反应调节中的作用，在该模型中，Hh 受体基因 Patched-1 的半合子失活导致 Hh 反应基因的组成性激活。与来自野生型（wt）同窝仔鼠的对照细胞相比，脾和淋巴结（LN）T 细胞的体外 TCR 刺激显示出 Th2 细胞因子（IL-4 和 IL-10）水平升高，表明 Hh 通路的激活有利于 Th2 表型。此外，CD4 细胞分泌的 IL-17 较少，Th1 表型的建立在 小鼠中受损。一致地，在实验性自身免疫性脑脊髓炎（EAE）诱导的炎症挑战中，与 wt 小鼠相比， 小鼠显示出较轻的临床评分和较少的脊髓损伤。这些结果表明 Hh/ptch 通路在免疫反应调节中的作用，并强调了 小鼠模型在研究 T 细胞介导的疾病和寻找炎症性疾病新的治疗策略方面的有用性。
