IFN-λ-诱导免疫相关GTP酶M介导中性粒细胞自噬在炎性肠病中的作用研究

Inflammatory Bowel Disease (IBD) is a group of chronic, relapsing inflammatory conditions of colon and small intestine. Neutrophils play dual roles in the IBD and the imbalance of different functional responses of neutrophils is linked with the pathogenesis of the disease, yet little is known about the mechanisms that regulate such balance. Genome-wide association study (GWAS) of IBD has suggested the single nucleotide polymorphism (SNP) of Immune-related GTPase (human: IRGM; mouse: Irgm1) is strongly associated with IBD risk. However, how Irgm1 is involved in the pathogenesis of IBD is still unclear. Our preliminary data has indicated that Irgm1 is mainly expressed by gut infiltrated neutrophils in a mouse model of IBD and is positively correlated with the expression of type three Interferon (IFN-λ). In addition, we demonstrated that IFN-λ can induce neutrophil autophagy through Irgm1 in vitro. More importantly, we observed that compared to wild-type mice, Irgm1-/- developed more severe IBD disease activity, which is associated with lower neutrophil autophagy activity and higher pro-inflammatory cytokines from neutrophils. Based on this, our proposed study will focus on how IFN-λ-Irgm1-autophagy may influence neutrophil function, which may in turn impact IBD disease course both from vitro and vivo perspectives. Our study will advance our understanding about the pathogenesis of IBD and provide solid experimental basis for developing neutrophil-targeting in IBD.

炎性肠病（IBD）是一类慢性复发性的肠道炎性疾病。在其发病过程中，中性粒细胞具有双面性，其功能失调对IBD发病起着重要作用。然而，人们对调节中性粒细胞功能平衡的具体分子机制仍知之甚少。全基因组关联分析研究（GWAS）表明免疫相关GTP酶M(人:IRGM，鼠：Irgm1)的基因多态性与IBD发病高度相关。然而IRGM在IBD中的作用依然有待研究。我们前期工作发现在IBD小鼠模型中，Irgm1高表达于浸润肠道的中性粒细胞，并受IFN-λ调控。我们还证实Irgm1参与IFN-λ诱导的中性粒细胞自噬。更重要的是：与野生型小鼠相比，Irgm1-/-小鼠IBD发病明显加重，而这可能与Irgm1-/-中性粒细胞自噬功能的降低及促炎细胞因子表达增高有关。由此，本课题从IFN-λ-Irgm1-自噬轴入手，从体内、外两方面研究中性粒细胞参与IBD的发病机制，为以中性粒细胞为靶点的临床治疗提供重要依据。

炎性肠病(IBD)是一类慢性复发性的肠道炎性疾病，病因不明，且目前治疗手段相对单一。有研究表明：IFN-λ（III型干扰素）可能成为新型治疗IBD的手段之一。目前认为IFN-λ主要通过调控中性粒细胞的功能治疗IBD。然而，人们对于IFN-λ是如何调节中性粒细胞功能的具体 分子机制仍知之甚少。有研究表明免疫相关GTP酶M(人:IRGM，鼠:Irgm1)的基因多态性与IBD发病高度相关。然而IRGM在IBD中的作用依然有待研究。通过本项目的研究，我们首先发现。在人类炎性肠病以及小鼠模型中，IRGM/Irgm1高表达于浸润肠道的中性粒细胞。在特异性敲除中性粒细胞IFN-λ受体后，中性粒细胞Irgm1明显降低，提示IFN-λ是中性粒细胞Irgm1表达调控分子。此外，我们还发现：当特异性敲除小鼠中性粒细胞Irgm1后，小鼠IBD的发病明显加重，并且对IFN-λ的治疗无效。相关机制研究进一步揭示，Irgm1参与调控中性粒细胞自噬，并且其通过自噬降解NLRP3炎性小体，继而降低中性粒细胞在IBD中的致病功能，避免中性粒细胞的过度活化。本项目的完成揭示了中性粒细胞参与IBD的发 病的新功能，明确了IFN-λ治疗炎性肠病的新机制、为以中性粒细胞为靶点的临床治疗提供重要依据。