Rh-relaxin-2 attenuates degranulation of mast cells by inhibiting NF-κB through PI3K-AKT/TNFAIP3 pathway in an experimental germinal matrix hemorrhage rat model
Open Access
- 28 August 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Neuroinflammation
- Vol. 17 (1), 1-12
- https://doi.org/10.1186/s12974-020-01926-x
Abstract
Mast cells play an important role in early immune reactions in the brain by degranulation and the consequent inflammatory response. Our aim of the study is to investigate the effects of rh-relaxin-2 on mast cells and the underlying mechanisms in a germinal matrix hemorrhage (GMH) rat model. One hundred seventy-three P7 rat pups were subjected to GMH by an intraparenchymal injection of bacterial collagenase. Clodronate liposome was administered through intracerebroventricular (i.c.v.) injections 24 h prior to GMH to inhibit microglia. Rh-relaxin-2 was administered intraperitoneally at 1 h and 13 h after GMH. Small interfering RNA of RXFP1 and PI3K inhibitor LY294002 were given by i.c.v. injection. Post-GMH evaluation included neurobehavioral function, Western blot analysis, immunofluorescence, Nissl staining, and toluidine blue staining. Our results demonstrated that endogenous relaxin-2 was downregulated and that RXFP1 level peaked on the first day after GMH. Administration of rh-relaxin-2 improved neurological functions, attenuated degranulation of mast cells and neuroinflammation, and ameliorated post-hemorrhagic hydrocephalus (PHH) after GMH. These effects were associated with RXFP1 activation, increased expression of PI3K, phosphorylated AKT and TNFAIP3, and decreased levels of phosphorylated NF-κB, tryptase, chymase, IL-6, and TNF-α. However, knockdown of RXFP1 and PI3K inhibition abolished the protective effects of rh-relaxin-2. Our findings showed that rh-relaxin-2 attenuated degranulation of mast cells and neuroinflammation, improved neurological outcomes, and ameliorated hydrocephalus after GMH through RXFP1/PI3K-AKT/TNFAIP3/NF-κB signaling pathway.Funding Information
- R21 (NS101284)
- NS (81301098)
- Traumatic research center of Yunan Province (2018NS279, 2018NS280)
This publication has 25 references indexed in Scilit:
- The relaxin receptor as a therapeutic target - perspectives from evolution Cheek for updates and drug targetingPharmacology & Therapeutics, 2018
- Biliverdin reductase-A attenuated GMH-induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS/NO pathwayJournal of Neuroinflammation, 2018
- Opportunities in posthemorrhagic hydrocephalus research: outcomes of the Hydrocephalus Association Posthemorrhagic Hydrocephalus WorkshopFluids and Barriers of the CNS, 2018
- Melatonin Alleviates Intracerebral Hemorrhage-Induced Secondary Brain Injury in Rats via Suppressing Apoptosis, Inflammation, Oxidative Stress, DNA Damage, and Mitochondria InjuryTranslational Stroke Research, 2017
- Mast cells in neuroinflammation and brain disordersNeuroscience & Biobehavioral Reviews, 2017
- Early Anti-inflammatory and Pro-angiogenic Myocardial Effects of Intravenous Serelaxin Infusion for 72 H in an Experimental Rat Model of Acute Myocardial InfarctionJournal of Cardiovascular Translational Research, 2017
- The Role of Mast Cells in Intracerebral HemorrhageNeurocritical Care, 2017
- Mast cells on the mind: new insights and opportunitiesTrends in Neurosciences, 2013
- Rodent neonatal germinal matrix hemorrhage mimics the human brain injury, neurological consequences, and post-hemorrhagic hydrocephalusExperimental Neurology, 2012
- Relaxin Family Peptides and Receptors in Mammalian BrainAnnals of the New York Academy of Sciences, 2009