Inhibition of monocyte production using siRNA against CD115 and M-CSF in autoimmune myocarditis

单核细胞和巨噬细胞主要参与各种疾病的进展。申请人最近能够证明，针对CCR2的纳米颗粒包裹的siRNA可以防止单核细胞在病变部位聚集。在迄今尚未发表的实验中，人们发现这种新开发的纳米颗粒也定位于产生单核细胞的髓系祖细胞。这些髓系祖细胞和单核细胞都表达集落刺激因子1受体(CD115)，它与M-CSF结合，M-CSF是单核细胞产生、增殖和分化所必需的细胞因子。本研究的目的是通过纳米颗粒包裹的siRNA选择性地沉默髓系祖细胞和单核细胞中CD115的产生。其次，由于单核细胞本身是M-CSF的主要产生者，将探索另一种siRNA来阻止细胞因子的合成。在体外和体内验证实验之后，如果通过siRNA纳米颗粒减少单核细胞的产生导致心脏炎症的减少并影响疾病的结局，它将在自身免疫性心肌炎的小鼠模型中进行测试。这种新的方法可以促进髓系细胞谱系的独占调节，并在免疫治疗中提供新的治疗选择。

Monocytes and macrophages are centrally involved in the progression of various diseases. The applicant was recently able to show that nanoparticle encapsulated siRNA against CCR2 prevents the accumulation of monocytes at the site of lesion. In so far unpublished experiments it was found that this newly developed nanoparticle also localizes to monocyte-producing myeloid progenitor cells. These myeloid progenitor cells, as well as monocytes express Colony Stimulating Factor 1 Receptor (CD115), which binds M-CSF, a cytokine essential for the production, proliferation and differentiation of monocytes.Aim of the here proposed project is to selectively reduce the production of monocytes by silencing CD115 in myeloid progenitors cells and monocytes with nanoparticle encapsulated siRNA. Secondly, with monocytes being main producers of M-CSF themselves, an additional siRNA will be explored to block the synthesis of the cytokine. Following ex vivo- and in vivo- validation experiments it will be tested in the mouse model of autoimmune myocarditis if reduced monocyte production through siRNA-nanoparticles results in a reduction of cardiac inflammation and impacts the outcome of disease.This new approach could facilitate the exclusive modulation of the myeloid cell lineage and offer new therapeutic options in immune therapy.