Restricted accessResearch articleFirst published online 2023-07
ADAM17 Aggravates the Inflammatory Response by Modulating Microglia Polarization Through the TGF-β1/Smad Pathway Following Experimental Traumatic Brain Injury
Microglia-mediated neuroinflammatory responses play important roles in secondary neurological injury after traumatic brain injury (TBI). The TGF-β pathway participates in the regulation of M1/M2 phenotype transformation of microglia. TGF-β can activate the Smad pathway by binding to TGF-βRs, which is regulated by the cleavage function of A disintegrin and metalloproteinase 17 (ADAM17). However, the role of ADAM17 and the associated signaling pathways in the pathological process after TBI remain unclear. Herein, we assessed the transformation of microglia M1/M2 phenotype polarization and the neuroinflammatory response after the inhibition of ADAM17. The formation of TGF-βRs and TGF-β1/TGF-βRII complexes on microglia were detected to evaluate the effect of ADAM17 inhibition on the TGF-β1/Smad pathway. ADAM17 was highly expressed after TBI and mainly located in the microglia. the inhibition of ADAM17 improved neurological function after TBI. The neuroprotective effect of ADAM17 inhibition was related to a shift from the M1 microglial phenotype to the M2 microglial phenotype, thus reducing TBI-induced neuroinflammation. ADAM17 inhibition increased expression of TGF-βRs on the microglia membrane, promoted formation of TGF-β1/TGF-βRII complexes, and induced intranuclear translocation of Smads, which activated the TGF-β/Smad pathway. In conclusion, our study suggested that ADAM17 inhibition regulated microglia M1/M2 phenotype polarization through the TGF-β1/Smad pathway and influenced the neuroinflammatory response after TBI.
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References
1.
SandsmarkDK, BashirA, WellingtonCL, et al.Cerebral microvascular injury: a potentially treatable endophenotype of traumatic brain injury-induced neurodegeneration. Neuron, 2019; 103(3):367–379; doi: 10.1016/j.neuron.2019.06.002
2.
CorpsKN, RothTL, McGavernDB. Inflammation and neuroprotection in traumatic brain injury. JAMA Neurol, 2015; 72(3):355–362; doi: 10.1001/jamaneurol.2014.3558
3.
JassamYN, IzzyS, WhalenM, et al.Neuroimmunology of traumatic brain injury: time for a paradigm shift. Neuron, 2017; 95(6):1246–1265; doi: 10.1016/j.neuron.2017.07.010
4.
ShandraO, WinemillerAR, HeithoffBP, et al.Repetitive diffuse mild traumatic brain injury causes an atypical astrocyte response and spontaneous recurrent seizures. J Neurosci, 2019; 39(10):1944–1963; doi: 10.1523/jneurosci.1067-18.2018
5.
HenryRJ, RitzelRM, BarrettJP, et al.Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits. J Neurosci, 2020; 40(14):2960–2974; doi: 10.1523/jneurosci.2402-19.2020
6.
XiongXY, LiuL, YangQW. Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. Prog Neurobiol, 2016; 142:23-44; doi: 10.1016/j.pneurobio.2016.05.001
7.
MaY, WangJ, WangY, et al.The biphasic function of microglia in ischemic stroke. Progress in neurobiology, 2017; 157:247–272; doi: 10.1016/j.pneurobio.2016.01.005
8.
WolfSA, BoddekeHW, KettenmannH. Microglia in Physiology and Disease. Annual review of physiology, 2017; 79:619–643; doi: 10.1146/annurev-physiol-022516-034406
9.
TangY, LeW. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol, 2016; 53(2):1181–1194; doi: 10.1007/s12035-014-9070-5
10.
HenekaMT, CarsonMJ, El KhouryJ, et al.Neuroinflammation in Alzheimer's disease. Lancet Neurol, 2015; 14(4):388–405; doi: 10.1016/s1474-4422(15)70016-5
11.
LiuZ, ChenHQ, HuangY, et al.Transforming growth factor-β1 acts via TβR-I on microglia to protect against MPP(+)-induced dopaminergic neuronal loss. Brain, behavior, and immunity, 2016; 51:131–143; doi: 10.1016/j.bbi.2015.08.006
12.
LanX, HanX, LiQ, et al.Modulators of microglial activation and polarization after intracerebral haemorrhage. Nat Rev Neurol, 2017; 13(7):420–433; doi: 10.1038/nrneurol.2017.69
EyolfsonE, KhanA, MychasiukR, et al.Microglia dynamics in adolescent traumatic brain injury. J Neuroinflammation, 2020; 17(1):326; doi: 10.1186/s12974-020-01994-z
15.
QinY, GarrisonBS, MaW, et al.A Milieu Molecule for TGF-β Required for microglia function in the nervous system. Cell, 2018; 174(1):156–171.e16; doi: 10.1016/j.cell.2018.05.027
16.
DevanneyNA, StewartAN, GenselJC. Microglia and macrophage metabolism in CNS injury and disease: the role of immunometabolism in neurodegeneration and neurotrauma. Exp Neurol, 2020; 329:113310; doi: 10.1016/j.expneurol.2020.113310
17.
HataA, ChenYG. TGF-β signaling from receptors to Smads. Cold Spring Harb Perspect Biol, 2016; 8(9); doi: 10.1101/cshperspect.a022061
18.
MengXM, Nikolic-PatersonDJ, LanHY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol, 2016; 12(6):325–338; doi: 10.1038/nrneph.2016.48
19.
MaciasMJ, Martin-MalpartidaP, MassaguéJ. Structural determinants of Smad function in TGF-β signaling. Trends in Biochem Sci, 2015; 40(6):296–308; doi: 10.1016/j.tibs.2015.03.012
20.
BlackRA, RauchCT, KozloskyCJ, et al.A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature, 1997; 385(6618):729–733; doi: 10.1038/385729a0
21.
PeschonJJ, SlackJL, ReddyP, et al.An essential role for ectodomain shedding in mammalian development. Science, 1998; 282(5392):1281–12804; doi: 10.1126/science.282.5392.1281
22.
MalapeiraJ, EsselensC, Bech-SerraJJ, et al.ADAM17 (TACE) regulates TGFβ signaling through the cleavage of vasorin. Oncogene, 2011; 30(16):1912–1922; doi: 10.1038/onc.2010.565
23.
Geribaldi-DoldánN, CarrascoM, Murillo-CarreteroM, et al.Specific inhibition of ADAM17/TACE promotes neurogenesis in the injured motor cortex. Cell Death Dis, 2018; 9(9):862; doi: 10.1038/s41419-018-0913-2
24.
SommerD, CorstjensI, SanchezS, et al.ADAM17-deficiency on microglia but not on macrophages promotes phagocytosis and functional recovery after spinal cord injury. Brain Behav Immun, 2019; 80:129–145; doi: 10.1016/j.bbi.2019.02.032
25.
ZhangS, KojicL, TsangM, et al.Distinct roles for metalloproteinases during traumatic brain injury. Neurochem Int, 2016; 96:46–55; doi: 10.1016/j.neuint.2016.02.013
26.
KawasakiK, FreimuthJ, MeyerDS, et al.Genetic variants of Adam17 differentially regulate TGFβ signaling to modify vascular pathology in mice and humans. Proc Natl Acad Sci U S A, 2014; 111(21):7723–7728; doi: 10.1073/pnas.1318761111
27.
OuSC, BaiKJ, ChengWH, et al.TGF-β Induced CTGF Expression in human lung epithelial cells through ERK, ADAM17, RSK1, and C/EBPβ pathways. Intl J Mol Sci, 2020; 21(23); doi: 10.3390/ijms21239084
28.
ChenCD, PodvinS, GillespieE, et al.Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci U S A, 2007; 104(50):19796–19801; doi: 10.1073/pnas.0709805104
29.
ChenX, ChenC, FanS, et al.Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway following experimental traumatic brain injury. J Neuroinflammation, 2018; 15(1):116; doi: 10.1186/s12974-018-1151-3
30.
ZhengS, WangC, LinL, et al.TNF-α impairs pericyte-mediated cerebral microcirculation via the NF-κB/iNOS axis after experimental traumatic brain injury. J Neurotrauma, 2022; doi: 10.1089/neu.2022.0016
31.
SchumacherN, Rose-JohnS. ADAM17 activity and IL-6 trans-signaling in inflammation and cancer. Cancers (Basel), 2019; 11(11); doi: 10.3390/cancers11111736
32.
VidalPM, LemmensE, AvilaA, et al.ADAM17 is a survival factor for microglial cells in vitro and in vivo after spinal cord injury in mice. Cell Death Dis, 2013; 4(12):e954; doi: 10.1038/cddis.2013.466
33.
CaponeC, DabertrandF, Baron-MenguyC, et al.Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics. eLife, 2016; 5; doi: 10.7554/eLife.17536
34.
ZouZ, LiL, LiQ, et al.The role of S100B/RAGE-enhanced ADAM17 activation in endothelial glycocalyx shedding after traumatic brain injury. J Neuroinflammation, 2022; 19(1):46; doi: 10.1186/s12974-022-02412-2
35.
HeXY, DanQQ, WangF, et al.Protein network analysis of the serum and their functional implication in patients subjected to traumatic brain injury. Front Neurosci, 2018; 12:1049; doi: 10.3389/fnins.2018.01049
36.
ArenasYM, Cabrera-PastorA, JuciuteN, et al.Blocking glycine receptors reduces neuroinflammation and restores neurotransmission in cerebellum through ADAM17-TNFR1-NF-κβ pathway. J Neuroinflammation, 2020; 17(1):269; doi: 10.1186/s12974-020-01941-y
37.
BlobelCP. ADAMs: key components in EGFR signalling and development. Nature reviews Molecular cell biology, 2005; 6(1):32–43; doi: 10.1038/nrm1548
38.
PatelRK, PrasadN, KuwarR, et al.Transforming growth factor-beta 1 signaling regulates neuroinflammation and apoptosis in mild traumatic brain injury. Brain, behavior, and immunity, 2017; 64:244–258; doi: 10.1016/j.bbi.2017.04.012
39.
ChioCC, LinMT, ChangCP, et al.A positive correlation exists between neurotrauma and TGF-β1-containing microglia in rats. Eur J Clin Invest, 2016; 46(12):1063–1069; doi: 10.1111/eci.12693
40.
LiZ, XiaoJ, XuX, et al.M-CSF, IL-6, and TGF-β promote generation of a new subset of tissue repair macrophage for traumatic brain injury recovery. Sci Adv, 2021; 7(11); doi: 10.1126/sciadv.abb6260
41.
JiangQ, WeiD, HeX, et al.Phillyrin prevents neuroinflammation-induced blood-brain barrier damage following traumatic brain injury via altering microglial polarization. Front Pharmacol, 2021; 12:719823; doi: 10.3389/fphar.2021.719823
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