PMID- 30445446 OWN - NLM STAT- MEDLINE DCOM- 20190805 LR - 20190805 IS - 1876-4479 (Electronic) IS - 1873-9946 (Linking) VI - 13 IP - 4 DP - 2019 Mar 30 TI - A Molecular Targeted Immunotherapeutic Strategy for Ulcerative Colitis via Dual-targeting Nanoparticles Delivering miR-146b to Intestinal Macrophages. PG - 482-494 LID - 10.1093/ecco-jcc/jjy181 [doi] AB - 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-alpha, IL-6, and IL-1beta. 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. CI - Copyright (c) 2018 European Crohn's and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com. FAU - Deng, Feihong AU - Deng F AD - Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China. AD - Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China. FAU - He, Shuying AU - He S AD - Department of Gastroenterology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China. FAU - Cui, Shudan AU - Cui S AD - Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China. FAU - Shi, Yanqiang AU - Shi Y AD - Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China. FAU - Tan, Yuyong AU - Tan Y AD - Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - Li, Zhijun AU - Li Z AD - Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China. FAU - Huang, Chongyang AU - Huang C AD - Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China. FAU - Liu, Deliang AU - Liu D AD - Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - Zhi, Fachao AU - Zhi F AD - Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China. FAU - Peng, Liang AU - Peng L AD - Department of Gastroenterology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China. LA - eng PT - Journal Article PL - England TA - J Crohns Colitis JT - Journal of Crohn's & colitis JID - 101318676 RN - 0 (IL10 protein, mouse) RN - 0 (MicroRNAs) RN - 0 (Mirn146 microRNA, mouse) RN - 0 (STAT3 Transcription Factor) RN - 0 (Stat3 protein, mouse) RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 4) RN - 130068-27-8 (Interleukin-10) RN - 9042-14-2 (Dextran Sulfate) MH - Administration, Oral MH - Animals MH - Body Weight/drug effects MH - Carcinogenesis/drug effects MH - Cell Proliferation/drug effects MH - Colitis/chemically induced/*drug therapy/pathology/prevention & control MH - Colitis, Ulcerative/drug therapy MH - Dextran Sulfate MH - Disease Models, Animal MH - Immunotherapy/*methods MH - Interleukin-10/metabolism MH - Intestinal Mucosa/immunology/*physiopathology MH - Macrophage Activation/drug effects MH - Macrophages/*physiology MH - Male MH - Mice MH - MicroRNAs/administration & dosage/genetics/*therapeutic use MH - Molecular Targeted Therapy/*methods MH - Nanoparticles/therapeutic use MH - Phenotype MH - Regeneration/drug effects MH - STAT3 Transcription Factor/metabolism MH - Signal Transduction/drug effects MH - Toll-Like Receptor 4/antagonists & inhibitors OTO - NOTNLM OT - MTC nanoparticles OT - intestinal macrophages OT - miR-146b OT - mucosal repair OT - oral delivery EDAT- 2018/11/18 06:00 MHDA- 2019/08/06 06:00 CRDT- 2018/11/17 06:00 PHST- 2018/11/18 06:00 [pubmed] PHST- 2019/08/06 06:00 [medline] PHST- 2018/11/17 06:00 [entrez] AID - 5184562 [pii] AID - 10.1093/ecco-jcc/jjy181 [doi] PST - ppublish SO - J Crohns Colitis. 2019 Mar 30;13(4):482-494. doi: 10.1093/ecco-jcc/jjy181.