PMID- 30551457 OWN - NLM STAT- MEDLINE DCOM- 20190401 LR - 20190401 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 109 DP - 2019 Jan TI - Inhibition of TREM1 reduces inflammation and oxidative stress after spinal cord injury (SCI) associated with HO-1 expressions. PG - 2014-2021 LID - S0753-3322(18)34689-4 [pii] LID - 10.1016/j.biopha.2018.08.159 [doi] AB - Spinal cord injury (SCI) is a devastating event, leading to the progression of chronic neuropathic pain syndrome. Triggering receptor expressed on myeloid cells 1 (TREM1) is an innate immune receptor expressed on neutrophils and monocytes/macrophages. TREM1 enhances inflammatory response in various models of diseases, but its significance in SCI remains unclear. In the present study, we attempted to explore the effects of TREM1 on the regulation of SCI. Spinal cord contusion injury was performed in wild type (WT) and TREM1-knockout (TREM1(KO)) mice, and real time-quantitative PCR (RT-qPCR), western blot, and immunofluorescent (IF) staining were used to calculate TREM1, inflammation and oxidative stress in spinal cord tissues 42 days after SPII. In vitro, astrocytes (AST) and BV2 cells were transfected TREM siRNA or the negative control (NC) siRNA to knockdown (KD) TREM1 expressions, followed by lipopolysaccharide (LPS) stimulation to verify the role od TREM1 in modulating SPI. The results suggested that TREM1 was highly expressed in the spinal cord tissues of WT mice after SCI. TREM(KO) mice exhibited improved locomotor function, mechanical and thermal hypersensitivity in the hindpaws after SCI. In addition, peripheral nerve injury-related biomarkers were down-regulated by TREM1(KO) in SCI mice. TREM1(KO) increased NeuN-stained cells, and decreased GFAP and Iba-1 expressions in spinal cord tissues of mice after SCI. TREM1(KO) mice showed reduced expressions of inflammation-related regulators in the injured spinal cord. Further, toll like receptors (TLR-2, -3, -4, and -9), p-IkappaBalpha and p-nuclear factor-kappa B (NF-kappaB) protein expression levels were markedly decreased by TREM1(KO) in mice after SCI injury. Moreover, TREM-deficiency suppressed oxidative stress markers, while enhanced anti-oxidants, such as superoxide dismutase-1 (SOD1), NAD(P)H:quinone oxidoreductase-1 (NQO-1), heme oxygenase-1 (HO-1) and nuclear factor E2-related factor 2 (Nrf2) in the injured spinal cord. The in vivo results mentioned above were verified in LPS-stimulated AST and BV2 cells in vitro. Of note, the in vitro results also demonstrated that suppressing HO-1 expressions using Zn-protoporphyrin (ZnPP) abrogated TREM1(KD)-reduced inflammation, oxidative stress and glial cells activation. The results above demonstrated that suppressing TREM1 expressions markedly improved the outcome of SCI, most likely through reducing inflammation and oxidative stress at least partly regulated by HO-1 expressions. TREM1 inhibition might be therefore has potential as a therapeutic target after SCI. CI - Copyright (c) 2018. Published by Elsevier Masson SAS. FAU - Li, Zhenhuan AU - Li Z AD - Orthopedics Department, Zhabei Center Hospital of JingAn District of Shanghai, JingAn, Shanghai, 200070, China. FAU - Wu, Furong AU - Wu F AD - Tuberculosis Clinical Research Center, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, 200070, China. FAU - Xu, Dafeng AU - Xu D AD - Orthopedics Department, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Pudong, Shanghai, 201399, China. FAU - Zhi, Zhongzheng AU - Zhi Z AD - Orthopedics Department, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Pudong, Shanghai, 201399, China. FAU - Xu, Guanghui AU - Xu G AD - Orthopedics Department, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Pudong, Shanghai, 201399, China. Electronic address: 3375279225@qq.com. LA - eng PT - Journal Article DEP - 20181126 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 0 (Membrane Proteins) RN - 0 (RNA, Small Interfering) RN - 0 (TREM1 protein, mouse) RN - 0 (Triggering Receptor Expressed on Myeloid Cells-1) RN - EC 1.14.14.18 (Heme Oxygenase-1) RN - EC 1.14.14.18 (Hmox1 protein, mouse) SB - IM MH - Animals MH - Cell Line MH - Female MH - Heme Oxygenase-1/*biosynthesis MH - Inflammation/drug therapy/metabolism MH - Membrane Proteins/*biosynthesis MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Oxidative Stress/drug effects/*physiology MH - RNA, Small Interfering/pharmacology/therapeutic use MH - Spinal Cord Injuries/drug therapy/*metabolism MH - Triggering Receptor Expressed on Myeloid Cells-1/antagonists & inhibitors/*biosynthesis OTO - NOTNLM OT - HO-1 OT - Inflammation OT - Oxidative stress OT - Spinal cord injury (SCI) OT - TREM1 EDAT- 2018/12/16 06:00 MHDA- 2019/04/02 06:00 CRDT- 2018/12/16 06:00 PHST- 2018/07/07 00:00 [received] PHST- 2018/08/30 00:00 [revised] PHST- 2018/08/31 00:00 [accepted] PHST- 2018/12/16 06:00 [entrez] PHST- 2018/12/16 06:00 [pubmed] PHST- 2019/04/02 06:00 [medline] AID - S0753-3322(18)34689-4 [pii] AID - 10.1016/j.biopha.2018.08.159 [doi] PST - ppublish SO - Biomed Pharmacother. 2019 Jan;109:2014-2021. doi: 10.1016/j.biopha.2018.08.159. Epub 2018 Nov 26.