Feihong Deng1,2, Shuying He3, Shudan Cui2, Yanqiang Shi2, Yuyong Tan1, Zhijun Li2, Chongyang Huang2, Deliang Liu1, Fachao Zhi2, Liang Peng3. 1. Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China. 2. Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China. 3. Department of Gastroenterology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China.
Abstract
BACKGROUND AND AIMS: Macrophages are a promising therapeutic target for intestinal mucosal repair. MiR-146b appears to control macrophage activation and cell proliferation. METHODS: By loading miR-146b mimic on mannose-modified trimethyl chitosan [MTC]-conjugated nanoparticles [NPs] [MTC-miR146b], a molecular targeted immunotherapeutic approach was developed to selectively target intestinal macrophages for mucosal regeneration and tumourigenesis in mouse models. RESULTS: We first confirmed that miR-146b expression was significantly enhanced during mucosal regeneration in a murine colitis model. Moreover， after mucosal damage, MTC-miR146b mimic-treated wild-type mice had dramatically restored body weight and mucosal barrier function compared with MTC-NC treated mice. Strikingly, MTC-miR146b mimic oral administration protected miR-146b-deficient mice from dextran sodium sulphate [DSS] injury and the colitis-associated cancer process. Mechanistically, miR-146b strongly inhibited M1 macrophage activation by suppressing the Toll-like receptor 4 [TLR4] signalling pathway, resulting in the repression of the induction of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β. More importantly, miR-146b overexpression in bone marrow-derived macrophages [BMDMs] in M1 differentiation conditions induced a phenotype similar to M2 macrophages and improved the proliferation of co-cultured colonic epithelial cells via STAT3-dependent IL-10 production. CONCLUSIONS: MTC-miR146b should be regarded as an effective candidate for oral delivery and could improve the efficacy of immunotherapies for ulcerative colitis and colitis-associated cancer.
BACKGROUND AND AIMS: Macrophages are a promising therapeutic target for intestinal mucosal repair. MiR-146b appears to control macrophage activation and cell proliferation. METHODS: By loading miR-146b mimic on mannose-modified trimethyl chitosan [MTC]-conjugated nanoparticles [NPs] [MTC-miR146b], a molecular targeted immunotherapeutic approach was developed to selectively target intestinal macrophages for mucosal regeneration and tumourigenesis in mouse models. RESULTS: We first confirmed that miR-146b expression was significantly enhanced during mucosal regeneration in a murinecolitis model. Moreover， after mucosal damage, MTC-miR146b mimic-treated wild-type mice had dramatically restored body weight and mucosal barrier function compared with MTC-NC treated mice. Strikingly, MTC-miR146b mimic oral administration protected miR-146b-deficient mice from dextran sodium sulphate [DSS] injury and the colitis-associated cancer process. Mechanistically, miR-146b strongly inhibited M1 macrophage activation by suppressing the Toll-like receptor 4 [TLR4] signalling pathway, resulting in the repression of the induction of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β. More importantly, miR-146b overexpression in bone marrow-derived macrophages [BMDMs] in M1 differentiation conditions induced a phenotype similar to M2 macrophages and improved the proliferation of co-cultured colonic epithelial cells via STAT3-dependent IL-10 production. CONCLUSIONS: MTC-miR146b should be regarded as an effective candidate for oral delivery and could improve the efficacy of immunotherapies for ulcerative colitis and colitis-associated cancer.