Hematoma clearance by reactive microglia after intracerebral hemorrhage

Zhenhua Zhang^1†, Wei Xu^1,2†, Honghui Sheng¹, Leo Huang³, Jiaxin Zhang⁴, Lanting Zhang⁵, Limin Wang⁶, Junmin Wang¹, Xiuhua Ren^1*, Chao Jiang^7*, Jian Wang^1*

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¹ Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China

² School of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China

³ Department of Psychology, University of Toronto, Toronto, Ontario M5S 1A1, Canada

⁴ Saint John Paul the Great Catholic High School, Dumfries, VA 20026, USA

⁵ High School Division of Zhengzhou Middle School, Zhengzhou, Henan Province, China

⁶ Department of Neurology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangdong Neuroscience Institute, Guangzhou, China

⁷ Department of Neurology, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China

GPD 2023, 2(2), 336 https://doi.org/10.36922/gpd.336

Submitted: 26 January 2023 | Accepted: 20 March 2023 | Published: 30 March 2023

© 2023 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )

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Abstract

Intracerebral hemorrhage (ICH) is a subtype of stroke with high incidence rate and mortality. The pathogenesis of ICH involves primary brain injury and secondary brain injury. Unfortunately, no approved treatment options and therapies targeting them have shown satisfactory outcomes. Microglia are resident innate immune cells with phagocytic function in the central nervous system that rapidly respond to brain injury. Recent research has indicated that reactive microglia with enhanced phagocytosis reprogrammed by the interleukin 10 (IL-10) signaling pathway are critical for endogenous hematoma clearance. In this review, we first summarize the progress of microglial activation and function after ICH, focusing on specific microglial markers, pro- and anti-inflammatory molecules, as well as phenotypic and functional changes. The available evidence supports that microglia play a dual role after ICH. Second, we summarize the results of previous studies on hematoma clearance, focusing on reactive microglia in clearing hematoma through endogenous pathways reprogrammed by IL-10 or other molecules and necessitating the prospect of further research in this field. This review will help us better understand the role of reactive microglia in hematoma clearance and identify potential therapeutic targets to facilitate translational research in this direction.

Keywords

Intracerebral hemorrhage

Microglial/microphage

Inflammation

Anti-inflammation

Interleukin 10

Phagocytosis

Funding

None.

References

[1]

Wang J, 2010, Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol, 92(4): 463–477. https://doi.org/10.1016/j.pneurobio.2010.08.001

[2]

Wan J, Ren H, Wang J, 2019, Iron toxicity, lipid peroxidation and ferroptosis after intracerebral haemorrhage. Stroke Vasc Neurol, 4(2): 93–95. https://doi.org/10.1136/svn-2018-000205

[3]

An SJ, Kim TJ, Yoon BW, 2017, Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update. J Stroke, 19(1): 3–10. https://doi.org/10.5853/jos.2016.00864

[4]

Murphy SJ, Werring DJ, 2020, Stroke: Causes and clinical features. Med (Abingdon), 48(9): 561–566. https://doi.org/10.1016/j.mpmed.2020.06.002

[5]

Krishnamurthi RV, Feigin VL, Forouzanfar MH, et al., 2013, Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: Findings from the Global Burden of Disease Study 2010. Lancet Glob Health, 1(5): e259–e281 https://doi.org/10.1016/S2214-109X(13)70089-5

[6]

Feigin VL, Stark BA, Johnson CO, et al., 2021, Global, regional, and national burden of stroke and its risk factors, 1990-2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurology, 20(10): 795–820. https://doi.org/10.1016/S1474-4422(21)00252-0

[7]

Shi X, Bai H, Wang J, et al., 2021, Behavioral assessment of sensory, motor, emotion, and cognition in rodent models of intracerebral hemorrhage. Front Neurol, 12: 667511. https://doi.org/10.3389/fneur.2021.667511

[8]

Chang CF, Wan J, Li Q, et al., 2017, Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage. Neurobiol Dis, 103: 54–69. https://doi.org/10.1016/j.nbd.2017.03.016

[9]

Al-Kawaz MN, Hanley DF, Ziai W, 2020, Advances in therapeutic approaches for spontaneous intracerebral hemorrhage. Neurotherapeutics, 17(4): 1757–1767.https://doi.org/10.1007/s13311-020-00902-w

[10]

Jiang C, Guo H, Zhang Z, et al., 2022, Molecular, pathological, clinical, and therapeutic aspects of perihematomal edema in different stages of intracerebral hemorrhage. Oxid Med Cell Longev, 2022: 3948921. https://doi.org/10.1155/2022/3948921

[11]

Bai Q, Xue M, Yong VW, 2020, Microglia and macrophage phenotypes in intracerebral haemorrhage injury: Therapeutic opportunities. Brain, 143(5): 1297–1314. https://doi.org/10.1093/brain/awz393

[12]

Wang J, Dore S, 2007, Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab, 27(5): 894–908. https://doi.org/10.1038/sj.jcbfm.9600403

[13]

Wang M, Ye X, Hu J, et al., 2020, NOD1/RIP2 signalling enhances the microglia-driven inflammatory response and undergoes crosstalk with inflammatory cytokines to exacerbate brain damage following intracerebral haemorrhage in mice. J Neuroinflammation, 17(1): 364. https://doi.org/10.1186/s12974-020-02015-9

[14]

Song D, Yeh CT, Wang J, et al., 2022, Perspectives on the mechanism of pyroptosis after intracerebral hemorrhage. Front Immunol, 13: 989503. https://doi.org/10.3389/fimmu.2022.989503

[15]

Hanley DF, Thompson RE, Rosenblum M, et al., 2019, Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): A randomised, controlled, open-label, blinded endpoint phase 3 trial. Lancet, 393(10175): 1021–1032. https://doi.org/10.1016/s0140-6736(19)30195-3

[16]

Dastur CK, Yu WG, 2017, Current management of spontaneous intracerebral haemorrhage. Stroke Vasc Neurol, 2(1): e000047. https://doi.org/10.1136/svn-2016-000047

[17]

Thion M, Ginhoux F, Garel S, 2018, Microglia and early brain development: An intimate journey. Science, 362(6411): 185–189. https://doi.org/10.1126/science.aat0474

[18]

Zhang Z, Zhang Z, Lu H, et al., 2017, Microglial polarization and inflammatory mediators after intracerebral hemorrhage. Mol Neurobiol, 54(3): 1874–1886. https://doi.org/10.1007/s12035-016-9785-6

[19]

Min H, Jang YH, Cho IH, et al., 2016, Alternatively activated brain-infiltrating macrophages facilitate recovery from collagenase-induced intracerebral hemorrhage. Mol Brain, 9: 42. https://doi.org/10.1186/s13041-016-0225-3

[20]

Li Q, Lan X, Han X, et al., 2018, Expression of Tmem119/ Sall1 and Ccr2/CD69 in FACS-sorted microglia-and monocyte/macrophage-enriched cell populations after intracerebral hemorrhage. Front Cell Neurosci, 12: 520. https://doi.org/10.3389/fncel.2018.00520

[21]

Silvin A, Uderhardt S, Piot C, et al., 2022, Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration. Immunity, 55(8): 1448–1465.e6. https://doi.org/10.1016/j.immuni.2022.07.004

[22]

Liu J, Liu L, Wang X, et al., 2021, Microglia: A double-edged sword in intracerebral hemorrhage from basic mechanisms to clinical research. Front Immunol, 12: 675660. https://doi.org/10.3389/fimmu.2021.675660

[23]

Laffer B, Bauer D, Wasmuth S, et al., 2019, Loss of IL-10 promotes differentiation of microglia to a M1 phenotype. Front Cell Neurosci, 13: 430. https://doi.org/10.3389/fncel.2019.00430

[24]

Ren H, Han R, Chen X, et al., 2020, Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update. J Cereb Blood Flow Metab, 40(9): 1752–1768. https://doi.org/10.1177/0271678X20923551

[25]

Lan X, Han X, Liu X, et al., 2019, Inflammatory responses after intracerebral hemorrhage: From cellular function to therapeutic targets. J Cereb Blood Flow Metab, 39(1): 184–186. https://doi.org/10.1177/0271678X18805675

[26]

Lan X, Han X, Li Q, et al., 2017, Modulators of microglial activation and polarization after intracerebral haemorrhage. Nat Rev Neurol, 13(7): 420–433. https://doi.org/10.1038/nrneurol.2017.69

[27]

Sideris-Lampretsas G, Malcangio M, 2021, Microglial heterogeneity in chronic pain. Brain Behav Immun, 96: 279–289. https://doi.org/10.1016/j.bbi.2021.06.005

[28]

Silva NJ, Dorman LC, Vainchtein ID, et al., 2021, In situ and transcriptomic identification of microglia in synapse-rich regions of the developing Zebrafish brain. Nat Commun, 12(1): 5916. https://doi.org/10.1038/s41467-021-26206-x

[29]

Huarte OU, Kyriakis D, Heurtaux T, et al., 2021, Single-cell transcriptomics and in situ morphological analyses reveal microglia heterogeneity across the nigrostriatal pathway. Front Immunol, 12: 639613. https://doi.org/10.3389/fimmu.2021.639613

[30]

Barko K, Shelton M, Xue X, et al., 2022, Brain region-and sex-specific transcriptional profiles of microglia. Front Psychiatry, 13: 945548. https://doi.org/10.3389/fpsyt.2022.945548

[31]

Paolicelli RC, Sierra A, Stevens B, et al., 2022, Microglia states and nomenclature: A field at its crossroads. Neuron, 110(21): 3458–3483. https://doi.org/10.1016/j.neuron.2022.10.020

[32]

Spittau B, Dokalis N, Prinz M, 2020, The role of TGFβ signaling in microglia maturation and activation. Trends Immunol, 41(9): 836–848. https://doi.org/10.1016/j.it.2020.07.003

[33]

Grassivaro F, Martino G, Farina C, 2021, The phenotypic convergence between microglia and peripheral macrophages during development and neuroinflammation paves the way for new therapeutic perspectives. Neural Regen Res, 16(4): 635–637. https://doi.org/10.4103/1673-5374.295272

[34]

Jurga AM, Paleczna M, Kuter KZ, 2020, Overview of general and discriminating markers of differential microglia phenotypes. Front Cell Neurosci, 14: 198. https://doi.org/10.3389/fncel.2020.00198

[35]

Skytthe MK, Graversen JH, Moestrup SK, 2020, Targeting of CD163⁺macrophages in inflammatory and malignant diseases. Int J Mol Sci, 21(15): 5497. https://doi.org/10.3390/ijms21155497

[36]

Gantzel RH, Kjaer MB, Laursen TL, et al., 2020, Macrophage activation markers, soluble CD163 and mannose receptor, in liver fibrosis. Front Med (Lausanne), 7: 615599. https://doi.org/10.3389/fmed.2020.615599

[37]

Li Q, Weiland A, Chen X, et al., 2018, Ultrastructural characteristics of neuronal death and white matter injury in mouse brain tissues after intracerebral hemorrhage: Coexistence of ferroptosis, autophagy, and necrosis. Front Neurol, 9: 581. https://doi.org/10.3389/fneur.2018.00581

[38]

Sanchez-Molina P, Almolda B, Benseny-Cases N, et al., 2021, Specific microglial phagocytic phenotype and decrease of lipid oxidation in white matter areas during aging: Implications of different microenvironments. Neurobiol Aging, 105: 280–295. https://doi.org/10.1016/j.neurobiolaging.2021.03.015

[39]

Lan X, Han X, Li Q, et al., 2017, Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia. Brain Behav Immun, 61: 326–339. https://doi.org/10.1016/j.bbi.2016.12.012

[40]

Zhu H, Wang Z, Yu J, et al., 2019, Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage. Prog Neurobiol, 178: 101610. https://doi.org/10.1016/j.pneurobio.2019.03.003

[41]

Hua W, Chen X, Wang J, et al., 2020, Mechanisms and potential therapeutic targets for spontaneous intracerebral hemorrhage. Brain Hemorrhages, 1(2): 99–104. https://doi.org/10.1016/j.hest.2020.02.002

[42]

Wang J, Doré S, 2007, Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage. Brain, 130(Pt 6): 1643–1652. https://doi.org/10.1093/brain/awm095

[43]

Taylor RA, Chang CF, Goods BA, et al., 2017, TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage. J Clin Invest, 127(1): 280–292. https://doi.org/10.1172/JCI88647

[44]

Wang J, Rogove AD, Tsirka AE, et al., 2003, Protective role of tuftsin fragment 1-3 in an animal model of intracerebral hemorrhage. Ann Neurol, 54(5): 655–664. https://doi.org/10.1002/ana.10750

[45]

Li Q, Lan X, Han X, et al., 2021, Microglia-derived interleukin-10 accelerates post-intracerebral hemorrhage hematoma clearance by regulating CD36. Brain Behav Immun, 94: 437–457. https://doi.org/10.1016/j.bbi.2021.02.001

[46]

Xu J, Chen Z, Yu F, et al., 2020, IL-4/STAT6 signaling facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice. Proc Natl Acad Sci U S A, 117(51): 32679–32690. https://doi.org/10.1073/pnas.2018497117

[47]

Liu J, Li N, Zhu Z, et al., 2022, Vitamin D enhances hematoma clearance and neurologic recovery in intracerebral hemorrhage. Stroke, 53(6): 2058–2068. https://doi.org/10.1161/strokeaha.121.037769

[48]

Wilkinson DA, Keep RF, Hua Y, et al., 2018, Hematoma clearance as a therapeutic target in intracerebral hemorrhage: From macro to micro. J Cereb Blood Flow Metab, 38(4): 741– 745. https://doi.org/10.1177/0271678X17753590

[49]

Zhao X, Sun G, Ting SM, et al., 2015, Cleaning up after ICH: The role of Nrf2 in modulating microglia function and hematoma clearance. J Neurochem, 133(1): 144–152. https://doi.org/10.1111/jnc.12974

[50]

You M, Long C, Wan Y, et al., 2022, Neuron derived fractalkine promotes microglia to absorb hematoma via CD163/HO-1 after intracerebral hemorrhage. Cell Mol Life Sci, 79(5): 224. https://doi.org/10.1007/s00018-022-04212-6

[51]

Wang G, Li T, Duan SN, et al., 2018, PPAR-γ promotes hematoma clearance through haptoglobin-hemoglobin-CD163 in a rat model of intracerebral hemorrhage. Behav Neurol, 2018: 7646104. https://doi.org/10.1155/2018/7646104

[52]

Tao C, Keep RF, Xi G, et al., 2020, CD47 blocking antibody accelerates hematoma clearance after intracerebral hemorrhage in aged rats. Transl Stroke Res, 11(3): 541–551. https://doi.org/10.1007/s12975-019-00745-4

[53]

Yang Y, Wang P, Liu A, et al., 2022, Pulsed electromagnetic field protects against brain injury after intracerebral hemorrhage: Involvement of anti-inflammatory processes and hematoma clearance via CD36. J Mol Neurosci, 72(10): 2150–2161. https://doi.org/10.1007/s12031-022-02063-1

[54]

Siaw-Debrah F, Nyanzu M, Ni H, et al., 2017, Preclinical studies and translational applications of intracerebral hemorrhage. Biomed Res Int, 2017: 5135429. https://doi.org/10.1155/2017/5135429

[55]

Bedke T, Muscate F, Soukou S, et al., 2019, Title: IL-10- producing T cells and their dual functions. Semin Immunol, 44: 101335. https://doi.org/10.1016/j.smim.2019.101335

[56]

Song L, Xu LF, Pu ZX, et al., 2019, IL-10 inhibits apoptosis in brain tissue around the hematoma after ICH by inhibiting proNGF. Eur Rev Med Pharmacol Sci, 23(7): 3005–3011. https://doi.org/10.26355/eurrev_201904_17582

[57]

Li Q, Han X, Lan X, et al., 2017, Inhibition of neuronal ferroptosis protects hemorrhagic brain. JCI Insight, 2(7): e90777. https://doi.org/10.1172/jci.insight.90777

[58]

Yi S, Jiang X, Tang X, et al., 2020, IL-4 and IL-10 promotes phagocytic activity of microglia by up-regulation of TREM2. Cytotechnology, 72(4): 589–602. https://doi.org/10.1007/s10616-020-00409-4

[59]

Jiang C, Wang Y, Hu Q, et al., 2020, Immune changes in peripheral blood and hematoma of patients with intracerebral hemorrhage. FASEB J, 34(2): 2774–2791. https://doi.org/10.1096/fj.201902478R

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The authors declare that they have no competing interests.

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