PMID- 34171415 OWN - NLM STAT- MEDLINE DCOM- 20220124 LR - 20220124 IS - 1872-9754 (Electronic) IS - 0197-0186 (Linking) VI - 148 DP - 2021 Sep TI - Cathepsin C aggravates neuroinflammation via promoting production of CCL2 and CXCL2 in glial cells and neurons in a cryogenic brain lesion. PG - 105107 LID - S0197-0186(21)00153-4 [pii] LID - 10.1016/j.neuint.2021.105107 [doi] AB - OBJECTIVE: Chemokines regulate infiltration of immune cells to brain in inflammation. Cathepsin C (CatC), a lysosomal protease, has been found to participate in neuroinflammation. However, how CatC affects chemokines expression in neuroinflammation triggered by traumatic brain injury (TBI) remains unclear. Here, we investigated the effects of CatC on chemokines and neuroinflammation in TBI. METHODS: The present study used CatC knockdown (KD) and overexpression (OE) mice to generate cryogenic brain lesion model and determined effects of CatC on expression of chemokines CCL2, CCL5 and CXCL2 and infiltration of immune cells in acute and chronic phases of the lesion. Further, cellular sources of various chemokines were demonstrated in vitro. Values were compared with wild type (WT) mice. RESULTS: The results found that 6 h after lesion, CatC expression,IL-1beta and TNF-alpha mRNA and protein expression were strongly induced in the lesions; CCL2 and CXCL2 mRNA and protein expression were increased in CatC OE mice, while decreased in CatC KD mice. On the 3rd day after lesion, macrophages and neutrophils were mainly infiltrated to the lesions. Simultaneously, Iba-1+ cells in CatC OE mice were increased, while MPO + cells in CatC KD mice were decreased. In contrast, on the 28th day after lesion, a few lymphocytes were infiltrated surrounding new blood vessels. CatC OE mice showed larger volumes of scar areas, higher expression of CCL2,CXCL2,IL-1beta,TNF-alpha,IL-6 and iNOS, as well as stronger GFAP+ and Iba-1+ signals, while CatC KD mice had reversed effects. No significant differences of CCL5 expression were found in various genotype mice. Further, in vitro study demonstrated CatC-induced expression of CCL2 were mainly derived from microglia and neurons, while CXCL2 derived from microglia and astrocytes. CONCLUSION: Our data indicate that CatC aggravates neuroinflammation via promoting production of CCL2 and CXCL2 in glial cells and neurons in a cryogenic brain lesion, providing potential cellular and molecular targets for future intervention of TBI and other neuroinflammatory diseases. CI - Copyright (c) 2021 Elsevier Ltd. All rights reserved. FAU - Zhao, Xinnan AU - Zhao X AD - Department of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China. Electronic address: zhaonana1991@live.com. FAU - Liu, Shuang AU - Liu S AD - Department of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China. Electronic address: 741517237@qq.com. FAU - Yang, Xiaohan AU - Yang X AD - Department of Morphology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China. Electronic address: xiaohan-yxh@163.com. FAU - Liu, Yanna AU - Liu Y AD - Department of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China. Electronic address: liuyanna_7@hotmail.com. FAU - Liu, Gang AU - Liu G AD - Department of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China. Electronic address: 1957825811@qq.com. FAU - Fan, Kai AU - Fan K AD - Department of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China. Electronic address: 2286130554@qq.com. FAU - Ma, Jianmei AU - Ma J AD - Department of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China; National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning, China. Electronic address: ma_jianmei@hotmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210623 PL - England TA - Neurochem Int JT - Neurochemistry international JID - 8006959 RN - 0 (Ccl2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Chemokine CXCL2) RN - 0 (Chemokines) RN - 0 (Cxcl2 protein, mouse) RN - 0 (IL1B protein, mouse) RN - 0 (Interleukin-1beta) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 3.4.14.1 (Cathepsin C) SB - IM MH - Animals MH - Animals, Genetically Modified MH - Brain Injuries, Traumatic/*metabolism/*pathology MH - Cathepsin C/biosynthesis/*genetics MH - Chemokine CCL2/*metabolism MH - Chemokine CXCL2/*metabolism MH - Chemokines/metabolism MH - Freezing MH - Gene Expression Regulation MH - Gene Knockdown Techniques MH - Interleukin-1beta/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Neuroglia/*metabolism MH - Neuroinflammatory Diseases/*chemically induced/*metabolism MH - Neurons/*metabolism MH - Neutrophil Infiltration MH - Tumor Necrosis Factor-alpha/metabolism OTO - NOTNLM OT - CCL2 OT - CXCL2 OT - Cathepsin C OT - Neuroinflammation OT - Traumatic brain injury EDAT- 2021/06/26 06:00 MHDA- 2022/01/27 06:00 CRDT- 2021/06/25 20:13 PHST- 2020/11/24 00:00 [received] PHST- 2021/04/19 00:00 [revised] PHST- 2021/06/18 00:00 [accepted] PHST- 2021/06/26 06:00 [pubmed] PHST- 2022/01/27 06:00 [medline] PHST- 2021/06/25 20:13 [entrez] AID - S0197-0186(21)00153-4 [pii] AID - 10.1016/j.neuint.2021.105107 [doi] PST - ppublish SO - Neurochem Int. 2021 Sep;148:105107. doi: 10.1016/j.neuint.2021.105107. Epub 2021 Jun 23.