Neuron Derived Fractalkine Promotes Microglia to Absorb Hematoma Via CD163/HO-1 After Intracerebral Hemorrhage

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2022 Apr 7

PMID 35389112

Authors

Mingfeng You

Chunnan Long

Yan Wan

Hongxiu Guo

Jing Shen

Man Li

Quanwei He

Bo Hu

Affiliations

Soon will be listed here.

Abstract

Background: Hematoma leads to progressive neurological deficits and poor outcomes after intracerebral hemorrhage (ICH). Early clearance of hematoma is widely recognized as an essential treatment to limit the damage and improve the clinical prognosis. CD163, alias hemoglobin (Hb) scavenger receptor on microglia, plays a pivotal role in hematoma absorption, but CD163 on neurons permits Hb uptake and results in neurotoxicity. In this study, we focus on how to specially promote microglial but not neuronal CD163 mediated-Hb uptake and hematoma absorption.

Methods: RNA sequencing was used to explore the potential molecules involved in ICH progression, and hematoma was detected by magnetic resonance imaging (MRI). Western blot and immunofluorescence were used to evaluate the expression and location of fractalkine (FKN) after ICH. Erythrophagocytosis assay was performed to study the specific mechanism of action of FKN in hematoma clearance. Small interfering RNA (siRNA) transfection was used to explore the effect of peroxisome proliferator-activated receptor-γ (PPAR-γ) on hematoma absorption. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum FKN concentration in ICH patients.

Results: FKN was found to be significantly increased around the hematoma in a mouse model after ICH. With its unique receptor CX3CR1 in microglia, FKN significantly decreased the hematoma size and Hb content, and improved neurological deficits in vivo. Further, FKN could enhance erythrophagocytosis of microglia in vitro via the CD163/ hemeoxygenase-1 (HO-1) axis, while AZD8797 (a specific CX3CR1 inhibitor) reversed this effect. Moreover, PPAR-γ was found to mediate the increase in the CD163/HO-1 axis expression and erythrophagocytosis induced by FKN in microglia. Of note, a higher serum FKN level was found to be associated with better hematoma resolution in ICH patients.

Conclusions: We systematically identified that FKN may be a potential therapeutic target to improve hematoma absorption and we shed light on ICH treatment.

Citing Articles

Microglial Mechanisms and Therapeutic Potential in Brain Injury Post-Intracerebral Hemorrhage.

Gong Y, Li H, Cui H, Gong Y J Inflamm Res. 2025; 18:2955-2973.

PMID: 40026311 PMC: 11872102. DOI: 10.2147/JIR.S498809.

TRIOL attenuates intracerebral hemorrhage injury by bidirectionally modulating microglia- and neuron-mediated hematoma clearance.

Wei C, Chen C, Li S, Ding Y, Zhou Y, Mai F Redox Biol. 2025; 80:103487.

PMID: 39756315 PMC: 11758845. DOI: 10.1016/j.redox.2024.103487.

Fractalkine/CX3CR1 axis is critical for neuroprotection induced by hypoxic postconditioning against cerebral ischemic injury.

Zhan L, Qiu M, Zheng J, Lai M, Lin K, Dai J Cell Commun Signal. 2024; 22(1):457.

PMID: 39327578 PMC: 11426015. DOI: 10.1186/s12964-024-01830-4.

New targets in spontaneous intracerebral hemorrhage.

Chiang P, Tsai L, Tsai H Curr Opin Neurol. 2024; 38(1):10-17.

PMID: 39325041 PMC: 11706352. DOI: 10.1097/WCO.0000000000001325.

ACSL4-Mediated Ferroptosis and Its Potential Role in Central Nervous System Diseases and Injuries.

Jia B, Li J, Song Y, Luo C Int J Mol Sci. 2023; 24(12).

PMID: 37373168 PMC: 10298642. DOI: 10.3390/ijms241210021.

References

Zhao X, Sun G, Zhang J, Strong R, Song W, Gonzales N . Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor gamma in microglia/macrophages. Ann Neurol. 2007; 61(4):352-62. DOI: 10.1002/ana.21097. View

Shao A, Zhu Z, Li L, Zhang S, Zhang J . Emerging therapeutic targets associated with the immune system in patients with intracerebral haemorrhage (ICH): From mechanisms to translation. EBioMedicine. 2019; 45:615-623. PMC: 6642355. DOI: 10.1016/j.ebiom.2019.06.012. View

Finneran D, Nash K . Neuroinflammation and fractalkine signaling in Alzheimer's disease. J Neuroinflammation. 2019; 16(1):30. PMC: 6371521. DOI: 10.1186/s12974-019-1412-9. View

Xie W, Yu H, Zhang Y, Liu Q, Meng H . CD163 promotes hematoma absorption and improves neurological functions in patients with intracerebral hemorrhage. Neural Regen Res. 2016; 11(7):1122-7. PMC: 4994455. DOI: 10.4103/1673-5374.187047. View

Cipriani R, Villa P, Chece G, Lauro C, Paladini A, Micotti E . CX3CL1 is neuroprotective in permanent focal cerebral ischemia in rodents. J Neurosci. 2011; 31(45):16327-35. PMC: 6633249. DOI: 10.1523/JNEUROSCI.3611-11.2011. View

Zhao X, Grotta J, Gonzales N, Aronowski J . Hematoma resolution as a therapeutic target: the role of microglia/macrophages. Stroke. 2008; 40(3 Suppl):S92-4. DOI: 10.1161/STROKEAHA.108.533158. View

Bulters D, Gaastra B, Zolnourian A, Alexander S, Ren D, Blackburn S . Haemoglobin scavenging in intracranial bleeding: biology and clinical implications. Nat Rev Neurol. 2018; 14(7):416-432. DOI: 10.1038/s41582-018-0020-0. View

Shi S, Li Y, Shi K, Wood K, Ducruet A, Liu Q . IL (Interleukin)-15 Bridges Astrocyte-Microglia Crosstalk and Exacerbates Brain Injury Following Intracerebral Hemorrhage. Stroke. 2020; 51(3):967-974. DOI: 10.1161/STROKEAHA.119.028638. View

An S, Kim T, Yoon B . Epidemiology, Risk Factors, and Clinical Features of Intracerebral Hemorrhage: An Update. J Stroke. 2017; 19(1):3-10. PMC: 5307940. DOI: 10.5853/jos.2016.00864. View

10.

Chen Y, Zhu G, Liu D, Zhang X, Liu Y, Yuan T . Subthalamic nucleus deep brain stimulation suppresses neuroinflammation by Fractalkine pathway in Parkinson's disease rat model. Brain Behav Immun. 2020; 90:16-25. DOI: 10.1016/j.bbi.2020.07.035. View

11.

Cai W, Yang T, Liu H, Han L, Zhang K, Hu X . Peroxisome proliferator-activated receptor γ (PPARγ): A master gatekeeper in CNS injury and repair. Prog Neurobiol. 2017; 163-164:27-58. PMC: 6037317. DOI: 10.1016/j.pneurobio.2017.10.002. View

12.

Reaux-Le Goazigo A, Steenwinckel J, Rostene W, Melik Parsadaniantz S . Current status of chemokines in the adult CNS. Prog Neurobiol. 2013; 104:67-92. DOI: 10.1016/j.pneurobio.2013.02.001. View

13.

Mendelow A, Gregson B, Rowan E, Murray G, Gholkar A, Mitchell P . Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet. 2013; 382(9890):397-408. PMC: 3906609. DOI: 10.1016/S0140-6736(13)60986-1. View

14.

Zhu H, Wang Z, Yu J, Yang X, He F, Liu Z . Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage. Prog Neurobiol. 2019; 178:101610. DOI: 10.1016/j.pneurobio.2019.03.003. View

15.

Zhao X, Kruzel M, Ting S, Sun G, Savitz S, Aronowski J . Optimized lactoferrin as a highly promising treatment for intracerebral hemorrhage: Pre-clinical experience. J Cereb Blood Flow Metab. 2020; 41(1):53-66. PMC: 7747168. DOI: 10.1177/0271678X20925667. View

16.

Ridderstad Wollberg A, Ericsson-Dahlstrand A, Jureus A, Ekerot P, Simon S, Nilsson M . Pharmacological inhibition of the chemokine receptor CX3CR1 attenuates disease in a chronic-relapsing rat model for multiple sclerosis. Proc Natl Acad Sci U S A. 2014; 111(14):5409-14. PMC: 3986185. DOI: 10.1073/pnas.1316510111. View

17.

Zolezzi J, Santos M, Bastias-Candia S, Pinto C, Godoy J, Inestrosa N . PPARs in the central nervous system: roles in neurodegeneration and neuroinflammation. Biol Rev Camb Philos Soc. 2017; 92(4):2046-2069. DOI: 10.1111/brv.12320. View

18.

Chen Z, Yu H, Li H, Shen H, Li X, Zhang J . Negative regulation of glial Tim-3 inhibits the secretion of inflammatory factors and modulates microglia to antiinflammatory phenotype after experimental intracerebral hemorrhage in rats. CNS Neurosci Ther. 2019; 25(6):674-684. PMC: 6515709. DOI: 10.1111/cns.13100. View

19.

Zhang J, Liu Y, Liu X, Li S, Cheng C, Chen S . Dynamic changes of CX3CL1/CX3CR1 axis during microglial activation and motor neuron loss in the spinal cord of ALS mouse model. Transl Neurodegener. 2019; 7:35. PMC: 6309063. DOI: 10.1186/s40035-018-0138-4. View

20.

Xing C, Lo E . Help-me signaling: Non-cell autonomous mechanisms of neuroprotection and neurorecovery. Prog Neurobiol. 2016; 152:181-199. PMC: 5064822. DOI: 10.1016/j.pneurobio.2016.04.004. View