INTRODUCTION: The choroid plexus is located in the cerebral ventricles. It consists of a stromal core and a single layer of cuboidal epithelial cells that forms the blood-cerebrospinal barrier. The main function of the choroid plexus is to produce cerebrospinal fluid. Subarachnoid hemorrhage due to aneurysm rupture is a devastating type of hemorrhagic stroke. Following subarachnoid hemorrhage, blood and the blood degradation products that disperse into the cerebrospinal fluid come in direct contact with choroid plexus epithelial cells. The aim of the current study was to elucidate the pathophysiological cascades responsible for the inflammatory reaction that is seen in the choroid plexus following subarachnoid hemorrhage. METHODS: Subarachnoid hemorrhage was induced in rats by injecting non-heparinized autologous blood to the cisterna magna. Increased intracranial pressure following subarachnoid hemorrhage was modeled by using artificial cerebrospinal fluid instead of blood. Subarachnoid hemorrhage and artificial cerebrospinal fluid animals were left to survive for 1, 3, 7 and 14 days. Immunohistochemical staining of TLR4, TLR9, FPR2, CCL2, TNFα, IL-1β, CCR2 and CX3CR1 was performed on the cryostat sections of choroid plexus tissue. The level of TLR4, TLR9, FPR2, CCL2, TNFα, IL-1β was detected by measuring immunofluorescence intensity in randomly selected epithelial cells. The number of CCR2 and CX3CR1 positive cells per choroid plexus area was manually counted. Immunohistochemical changes were confirmed by Western blot analyses. RESULTS: Immunohistochemical methods and Western blot showed increased levels of TLR9 and a slight increase in TLR4 and FRP2 following both subarachnoid hemorrhage as well as the application of artificial cerebrospinal fluid over time, although the individual periods were different. The levels of TNFα and IL-1β increased, while CCL2 level decreased slightly. Accumulation of macrophages positive for CCR2 and CX3CR1 was found in all periods after subarachnoid hemorrhage as well as after the application of artificial cerebrospinal fluid. DISCUSSION: Our results suggest that the inflammation develops in the choroid plexus and blood-cerebrospinal fluid barrier in response to blood components as well as acutely increased intracranial pressure following subarachnoid hemorrhage. These pro-inflammatory changes include accumulation in the choroid plexus of pro-inflammatory cytokines, innate immune receptors, and monocyte-derived macrophages.

Department of Anatomy Faculty of Medicine Masaryk University Brno Czechia

Department of Neurosurgery St Anne's University Hospital and Faculty of Medicine Masaryk University Brno Czechia

Institute of Biophysics Academy of Sciences of the Czech Republic Brno Czechia

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Akira S., Uematsu S., Takeuchi O. (2006). Pathogen recognition and innate immunity. Cell 124, 783–801. doi: 10.1016/j.cell.2006.02.015 PubMed DOI

Auffray C., Fogg D., Garfa M., Elain G., Join-Lambert O., Kayal S., et al. . (2007). Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317, 666–670. doi: 10.1126/science.1142883, PMID: PubMed DOI

Becker E. L., Forouhar F. A., Grunnet M. L., Boulay F., Tardif M., Bormann B. J., et al. . (1998). Broad immunocytochemical localization of the formylpeptide receptor in human organs, tissues, and cells. Cell Tissue Res. 292, 129–135. doi: 10.1007/s004410051042, PMID: PubMed DOI

Bederson J. B., Levy A. L., Ding W. H., Kahn R., DiPerna C. A., Jenkins A. L., et al. . (1998). Acute vasoconstriction after subarachnoid hemorrhage. Neurosurgery 42, 352–362. doi: 10.1097/00006123-199802000-00091, PMID: PubMed DOI

Benbenishty A., Gadrich M., Cottarelli A., Lubart A., Kain D., Amer M., et al. . (2019). Prophylactic TLR9 stimulation reduces brain metastasis through microglia activation. PLoS Biol. 17:e2006859. doi: 10.1371/journal.pbio.2006859, PMID: PubMed DOI PMC

Brazda V., Muller P., Brozkova K., Vojtesek B. (2006). Restoring wild-type conformation and DNA-binding activity of mutant p53 is insufficient for restoration of transcriptional activity. Biochem. Biophys. Res. Commun. 351, 499–506. doi: 10.1016/j.bbrc.2006.10.065, PMID: PubMed DOI

Buchanan M. M., Hutchinson M., Watkins L. R., Yin H. (2010). Toll-like receptor 4 in CNS pathologies. J. Neurochem. 114, 13–27. doi: 10.1111/j.1471-4159.2010.06736.x, PMID: PubMed DOI PMC

Cao Y., Chen J., Liu F., Qi G., Zhao Y., Xu S., et al. . (2023). Formyl peptide receptor 2 activation by mitochondrial formyl peptides stimulates the neutrophil proinflammatory response via the ERK pathway and exacerbates ischemia-reperfusion injury. Cell. Mol. Biol. Lett. 28:4. doi: 10.1186/s11658-023-00416-1, PMID: PubMed DOI PMC

Cazareth J., Guyon A., Heurteaux C., Chabry J., Petit-Paitel A. (2014). Molecular and cellular neuroinflammatory status of mouse brain after systemic lipopolysaccharide challenge: importance of CCR2/CCL2 signaling. J. Neuroinflammation 11:132. doi: 10.1186/1742-2094-11-132, PMID: PubMed DOI PMC

Combadiere C., Salzwedel K., Smith E. D., Tiffany H. L., Berger E. A., Murphy P. M. (1998). Identification of CX3CR1. A chemotactic receptor for the human CX3C chemokine fractalkine and a fusion coreceptor for HIV-1. J. Biol. Chem. 273, 23799–23804. doi: 10.1074/jbc.273.37.23799, PMID: PubMed DOI

Conductier G., Blondeau N., Guyon A., Nahon J.-L., Rovère C. (2010). The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. J. Neuroimmunol. 224, 93–100. doi: 10.1016/j.jneuroim.2010.05.010, PMID: PubMed DOI

Connolly E. S., Rabinstein A. A., Carhuapoma J. R., Derdeyn C. P., Dion J., Higashida R. T., et al. . (2012). Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke 43, 1711–1737. doi: 10.1161/STR.0b013e3182587839 PubMed DOI

d’Avella D., Cicciarello R., Zuccarello M., Albiero F., Romano A., Angileri F. F., et al. . (1996). Brain energy metabolism in the acute stage of experimental subarachnoid haemorrhage: local changes in cerebral glucose utilization. Acta Neurochir. 138:737–743; discussion 744. doi: 10.1007/BF01411481, PMID: PubMed DOI

Deshmane S. L., Kremlev S., Amini S., Sawaya B. E. (2009). Monocyte chemoattractant Protein-1 (MCP-1): an overview. J. Interf. Cytokine Res. 29, 313–326. doi: 10.1089/jir.2008.0027, PMID: PubMed DOI PMC

Dubový P., Brázda V., Klusáková I., Hradilová-Svíženská I. (2013). Bilateral elevation of interleukin-6 protein and mRNA in both lumbar and cervical dorsal root ganglia following unilateral chronic compression injury of the sciatic nerve. J. Neuroinflammation 10:55. doi: 10.1186/1742-2094-10-55, PMID: PubMed DOI PMC

Dubový P., Klusáková I., Svízenská I. (2002). A quantitative immunohistochemical study of the endoneurium in the rat dorsal and ventral spinal roots. Histochem. Cell Biol. 117, 473–480. doi: 10.1007/s00418-002-0411-5, PMID: PubMed DOI

Dufton N., Perretti M. (2010). Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists. Pharmacol. Ther. 127, 175–188. doi: 10.1016/j.pharmthera.2010.04.010, PMID: PubMed DOI

Etminan N., Chang H.-S., Hackenberg K., de Rooij N. K., Vergouwen M. D. I., Rinkel G. J. E., et al. . (2019). Worldwide incidence of aneurysmal subarachnoid hemorrhage according to region, time period, blood pressure, and smoking prevalence in the population: A systematic review and Meta-analysis. JAMA Neurol. 76, 588–597. doi: 10.1001/jamaneurol.2019.0006, PMID: PubMed DOI PMC

Figueiredo R. T., Fernandez P. L., Mourao-Sa D. S., Porto B. N., Dutra F. F., Alves L. S., et al. . (2007). Characterization of heme as activator of toll-like receptor 4. J. Biol. Chem. 282, 20221–20229. doi: 10.1074/jbc.M610737200, PMID: PubMed DOI

Geng J., Shi Y., Zhang J., Yang B., Wang P., Yuan W., et al. . (2021). TLR4 signalling via Piezo1 engages and enhances the macrophage mediated host response during bacterial infection. Nat. Commun. 12:3519. doi: 10.1038/s41467-021-23683-y, PMID: PubMed DOI PMC

Gram M., Sveinsdottir S., Cinthio M., Sveinsdottir K., Hansson S. R., Mörgelin M., et al. . (2014). Extracellular hemoglobin - mediator of inflammation and cell death in the choroid plexus following preterm intraventricular hemorrhage. J. Neuroinflammation 11:200. doi: 10.1186/s12974-014-0200-9, PMID: PubMed DOI PMC

Gregoriades J. M. C., Madaris A., Alvarez F. J., Alvarez-Leefmans F. J. (2019). Genetic and pharmacological inactivation of apical Na+-K+-2Cl- cotransporter 1 in choroid plexus epithelial cells reveals the physiological function of the cotransporter. Am. J. Physiol. Cell Physiol. 316, C525–C544. doi: 10.1152/ajpcell.00026.2018, PMID: PubMed DOI PMC

Guo Z., Hu Q., Xu L., Guo Z.-N., Ou Y., He Y., et al. . (2016). Lipoxin A4 reduces inflammation through formyl peptide receptor 2/p38 MAPK signaling pathway in subarachnoid hemorrhage rats. Stroke 47, 490–497. doi: 10.1161/STROKEAHA.115.011223, PMID: PubMed DOI PMC

Hernangómez M., Klusáková I., Joukal M., Hradilová-Svíženská I., Guaza C., Dubový P. (2016). CD200R1 agonist attenuates glial activation, inflammatory reactions, and hypersensitivity immediately after its intrathecal application in a rat neuropathic pain model. J. Neuroinflammation 13, 43–15. doi: 10.1186/s12974-016-0508-8, PMID: PubMed DOI PMC

Hylden J. L., Wilcox G. L. (1980). Intrathecal morphine in mice: a new technique. Eur. J. Pharmacol. 67, 313–316. doi: 10.1016/0014-2999(80)90515-4 PubMed DOI

Iwasaki A., Medzhitov R. (2004). Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5, 987–995. doi: 10.1038/ni1112 PubMed DOI

Jackowski A., Crockard A., Burnstock G., Russell R. R., Kristek F. (1990). The time course of intracranial pathophysiological changes following experimental subarachnoid haemorrhage in the rat. J. Cereb. Blood Flow Metab. 10, 835–849. doi: 10.1038/jcbfm.1990.140, PMID: PubMed DOI

Karimy J. K., Reeves B. C., Kahle K. T. (2020). Targeting TLR4-dependent inflammation in post-hemorrhagic brain injury. Expert Opin. Ther. Targets 24, 525–533. doi: 10.1080/14728222.2020.1752182, PMID: PubMed DOI PMC

Karimy J. K., Zhang J., Kurland D. B., Theriault B. C., Duran D., Stokum J. A., et al. . (2017). Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus. Nat. Med. 23, 997–1003. doi: 10.1038/nm.4361, PMID: PubMed DOI

Kaur C., Rathnasamy G., Ling E.-A. (2016). The choroid plexus in healthy and diseased brain. J. Neuropathol. Exp. Neurol. 75, 198–213. doi: 10.1093/jnen/nlv030, PMID: PubMed DOI

Khey K. M. W., Huard A., Mahmoud S. H. (2020). Inflammatory pathways following subarachnoid hemorrhage. Cell. Mol. Neurobiol. 40, 675–693. doi: 10.1007/s10571-019-00767-4 PubMed DOI PMC

Kwon M. S., Woo S. K., Kurland D. B., Yoon S. H., Palmer A. F., Banerjee U., et al. . (2015). Methemoglobin is an endogenous toll-like receptor 4 ligand-relevance to subarachnoid hemorrhage. Int. J. Mol. Sci. 16, 5028–5046. doi: 10.3390/ijms16035028 PubMed DOI PMC

Li L., Ni L., Heary R. F., Elkabes S. (2020). Astroglial TLR9 antagonism promotes chemotaxis and alternative activation of macrophages via modulation of astrocyte-derived signals: implications for spinal cord injury. J. Neuroinflammation 17, 1–18. doi: 10.1186/s12974-020-01748-x, PMID: PubMed DOI PMC

Lin T., Kwak Y. H., Sammy F., He P., Thundivalappil S., Sun G., et al. . (2010). Synergistic inflammation is induced by blood degradation products with microbial toll-like receptor agonists and is blocked by Hemopexin. J. Infect. Dis. 202, 624–632. doi: 10.1086/654929, PMID: PubMed DOI PMC

Ling E. A., Kaur C., Lu J. (1998). Origin, nature, and some functional considerations of intraventricular macrophages, with special reference to the epiplexus cells. Microsc. Res. Tech. 41, 43–56. doi: 10.1002/(SICI)1097-0029(19980401)41:1<43::AID-JEMT5>3.0.CO;2-V, PMID: PubMed DOI

Liszczak T. M., Black P. M., Tzouras A., Foley L., Zervas N. T. (1984). Morphological changes of the basilar artery, ventricles, and choroid plexus after experimental SAH. J. Neurosurg. 61, 486–493. doi: 10.3171/jns.1984.61.3.0486, PMID: PubMed DOI

Liu H., Hu J., Zheng Q., Feng X., Zhan F., Wang X., et al. . (2022). Piezo1 channels as force sensors in mechanical force-related chronic inflammation. Front. Immunol. 13:816149. doi: 10.3389/fimmu.2022.816149, PMID: PubMed DOI PMC

Liu C. S. C., Raychaudhuri D., Paul B., Chakrabarty Y., Ghosh A. R., Rahaman O., et al. . (2018). Cutting edge: Piezo1 Mechanosensors optimize human T cell activation. J. Immunol. 200, 1255–1260. doi: 10.4049/jimmunol.1701118, PMID: PubMed DOI

Llovera G., Benakis C., Enzmann G., Cai R., Arzberger T., Ghasemigharagoz A., et al. . (2017). The choroid plexus is a key cerebral invasion route for T cells after stroke. Acta Neuropathol. 134, 851–868. doi: 10.1007/s00401-017-1758-y, PMID: PubMed DOI

Mahad D., Callahan M. K., Williams K. A., Ubogu E. E., Kivisäkk P., Tucky B., et al. . (2006). Modulating CCR2 and CCL2 at the blood-brain barrier: relevance for multiple sclerosis pathogenesis. Brain 129, 212–223. doi: 10.1093/brain/awh655, PMID: PubMed DOI

Matz P., Turner C., Weinstein P. R., Massa S. M., Panter S. S., Sharp F. R. (1996). Heme-oxygenase-1 induction in glia throughout rat brain following experimental subarachnoid hemorrhage. Brain Res. 713, 211–222. doi: 10.1016/0006-8993(95)01511-6, PMID: PubMed DOI

Meghraoui-Kheddar A., Barthelemy S., Boissonnas A., Combadière C. (2020). Revising CX3CR1 expression on murine classical and non-classical monocytes. Front. Immunol. 11:1117. doi: 10.3389/fimmu.2020.01117, PMID: PubMed DOI PMC

Metzemaekers M., Gouwy M., Proost P. (2020). Neutrophil chemoattractant receptors in health and disease: double-edged swords. Cell. Mol. Immunol. 17, 433–450. doi: 10.1038/s41423-020-0412-0, PMID: PubMed DOI PMC

Mildner A., Mack M., Schmidt H., Brück W., Djukic M., Zabel M. D., et al. . (2009). CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132, 2487–2500. doi: 10.1093/brain/awp144, PMID: PubMed DOI

Miller B. A., Turan N., Chau M., Pradilla G. (2014). Inflammation, vasospasm, and brain injury after subarachnoid hemorrhage. Biomed. Res. Int. 2014:384342, 1–16. doi: 10.1155/2014/384342, PMID: PubMed DOI PMC

Miyake K. (2007). Innate immune sensing of pathogens and danger signals by cell surface toll-like receptors. Semin. Immunol. 19, 3–10. doi: 10.1016/j.smim.2006.12.002, PMID: PubMed DOI

Okada T., Suzuki H. (2017). Toll-like receptor 4 as a possible therapeutic target for delayed brain injuries after aneurysmal subarachnoid hemorrhage. Neural Regen. Res. 12, 193–196. doi: 10.4103/1673-5374.200795, PMID: PubMed DOI PMC

Pan P., Xu L., Zhang H., Liu Y., Lu X., Chen G., et al. . (2020). A review of hematoma components clearance mechanism after subarachnoid hemorrhage. Front. Neurosci. 14:685. doi: 10.3389/fnins.2020.00685, PMID: PubMed DOI PMC

Paradis A., Bernier S., Dumais N. (2016). TLR4 induces CCR7-dependent monocytes transmigration through the blood–brain barrier. J. Neuroimmunol. 295-296, 12–17. doi: 10.1016/j.jneuroim.2016.03.019, PMID: PubMed DOI

Piccinini A. M., Midwood K. S. (2010). DAMPening inflammation by modulating TLR Signalling. Mediat. Inflamm. 2010:e672395, 1–21. doi: 10.1155/2010/672395, PMID: PubMed DOI PMC

Prinz M., Priller J. (2010). Tickets to the brain: role of CCR2 and CX3CR1 in myeloid cell entry in the CNS. J. Neuroimmunol. 224, 80–84. doi: 10.1016/j.jneuroim.2010.05.015 PubMed DOI

Provencio J. J. (2013). Inflammation in subarachnoid hemorrhage and delayed deterioration associated with vasospasm: A review. Acta Neurochir. Suppl. 115, 233–238. doi: 10.1007/978-3-7091-1192-5_42, PMID: PubMed DOI PMC

Prunell G. F., Mathiesen T., Diemer N. H., Svendgaard N.-A. (2003). Experimental subarachnoid hemorrhage: subarachnoid blood volume, mortality rate, neuronal death, cerebral blood flow, and perfusion pressure in three different rat models. Neurosurgery 52:176. doi: 10.1097/00006123-200301000-00022, PMID: PubMed DOI

Prunell G. F., Mathiesen T., Svendgaard N.-A. (2002). A new experimental model in rats for study of the pathophysiology of subarachnoid hemorrhage. Neuroreport 13, 2553–2556. doi: 10.1097/00001756-200212200-00034, PMID: PubMed DOI

Reyes T. M., Walker J. R., DeCino C., Hogenesch J. B., Sawchenko P. E. (2003). Categorically distinct acute stressors elicit dissimilar transcriptional profiles in the paraventricular nucleus of the hypothalamus. J. Neurosci. 23, 5607–5616. doi: 10.1523/JNEUROSCI.23-13-05607.2003, PMID: PubMed DOI PMC

Saederup N., Cardona A. E., Croft K., Mizutani M., Cotleur A. C., Tsou C.-L., et al. . (2010). Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS One 5:e13693. doi: 10.1371/journal.pone.0013693, PMID: PubMed DOI PMC

Sasaki T., Kasuya H., Onda H., Sasahara A., Goto S., Hori T., et al. . (2004). Role of p38 mitogen-activated protein kinase on cerebral vasospasm after subarachnoid hemorrhage. Stroke 35, 1466–1470. doi: 10.1161/01.STR.0000127425.47266.20, PMID: PubMed DOI

Schwerk C., Rybarczyk K., Essmann F., Seibt A., Mölleken M.-L., Zeni P., et al. . (2010). TNFα induces choroid plexus epithelial cell barrier alterations by apoptotic and nonapoptotic mechanisms. J. Biomed. Biotechnol. 2010:307231. doi: 10.1155/2010/307231, PMID: PubMed DOI PMC

Sehba F. A., Pluta R. M., Zhang J. H. (2011). Metamorphosis of subarachnoid hemorrhage research: from delayed vasospasm to early brain injury. Mol. Neurobiol. 43, 27–40. doi: 10.1007/s12035-010-8155-z, PMID: PubMed DOI PMC

Shimada A., Hasegawa-Ishii S. (2021). Increased cytokine expression in the choroid plexus stroma and epithelium in response to endotoxin-induced systemic inflammation in mice. Toxicol. Rep. 8, 520–528. doi: 10.1016/j.toxrep.2021.03.002, PMID: PubMed DOI PMC

Silva M. T., do Vale A., dos Santos N. M. N. (2008). Secondary necrosis in multicellular animals: an outcome of apoptosis with pathogenic implications. Apoptosis 13, 463–482. doi: 10.1007/s10495-008-0187-8, PMID: PubMed DOI PMC

Simard P. F., Tosun C., Melnichenko L., Ivanova S., Gerzanich V., Simard J. M. (2011). Inflammation of the choroid plexus and ependymal layer of the ventricle following intraventricular hemorrhage. Transl. Stroke Res. 2, 227–231. doi: 10.1007/s12975-011-0070-8, PMID: PubMed DOI PMC

Skipor J., Szczepkowska A., Kowalewska M., Herman A. P., Lisiewski P. (2015). Profile of toll-like receptor mRNA expression in the choroid plexus in adult ewes. Acta Vet. Hung. 63, 69–78. doi: 10.1556/AVet.2014.027, PMID: PubMed DOI

Solár P., Brázda V., Levin S., Zamani A., Jančálek R., Dubový P., et al. . (2020a). Subarachnoid hemorrhage increases level of Heme Oxygenase-1 and Biliverdin reductase in the choroid plexus. Front. Cell. Neurosci. 14:593305. doi: 10.3389/fncel.2020.593305, PMID: PubMed DOI PMC

Solar P., Joukal M., Silar C., Jancalek R. (2022). Impact of analgesic regimen on patient outcome following subarachnoid hemorrhage: positive adjuvant effects of metamizole. Br. J. Neurosurg. 38, 1304–1311. doi: 10.1080/02688697.2022.2151563, PMID: PubMed DOI

Solár P., Klusáková I., Jančálek R., Dubový P., Joukal M. (2020b). Subarachnoid hemorrhage induces dynamic immune cell reactions in the choroid plexus. Front. Cell. Neurosci. 14:18. doi: 10.3389/fncel.2020.00018, PMID: PubMed DOI PMC

Solár P., Zamani A., Kubíčková L., Dubový P., Joukal M. (2020c). Choroid plexus and the blood–cerebrospinal fluid barrier in disease. Fluids Barriers CNS 17:35. doi: 10.1186/s12987-020-00196-2, PMID: PubMed DOI PMC

Solár P., Zamani A., Lakatosová K., Joukal M. (2022). The blood–brain barrier and the neurovascular unit in subarachnoid hemorrhage: molecular events and potential treatments. Fluids Barriers CNS 19:29. doi: 10.1186/s12987-022-00312-4, PMID: PubMed DOI PMC

Solomon R. A., Antunes J. L., Chen R. Y., Bland L., Chien S. (1985). Decrease in cerebral blood flow in rats after experimental subarachnoid hemorrhage: a new animal model. Stroke 16, 58–64. doi: 10.1161/01.str.16.1.58, PMID: PubMed DOI

Stridh L., Ek C. J., Wang X., Nilsson H., Mallard C. (2013). Regulation of toll-like receptors in the choroid plexus in the immature brain after systemic inflammatory stimuli. Transl. Stroke Res. 4, 220–227. doi: 10.1007/s12975-012-0248-8, PMID: PubMed DOI PMC

Talsma A. D., Niemi J. P., Pachter J. S., Zigmond R. E. (2022). The primary macrophage chemokine, CCL2, is not necessary after a peripheral nerve injury for macrophage recruitment and activation or for conditioning lesion enhanced peripheral regeneration. J. Neuroinflammation 19:179. doi: 10.1186/s12974-022-02497-9, PMID: PubMed DOI PMC

Thibeault I., Laflamme N., Rivest S. (2001). Regulation of the gene encoding the monocyte chemoattractant protein 1 (MCP-1) in the mouse and rat brain in response to circulating LPS and proinflammatory cytokines. J. Comp. Neurol. 434, 461–477. doi: 10.1002/cne.1187, PMID: PubMed DOI

Thompson D., Brissette C. A., Watt J. A. (2022). The choroid plexus and its role in the pathogenesis of neurological infections. Fluids Barriers CNS 19:75. doi: 10.1186/s12987-022-00372-6, PMID: PubMed DOI PMC

Tylek K., Trojan E., Regulska M., Lacivita E., Leopoldo M., Basta-Kaim A. (2021). Formyl peptide receptor 2, as an important target for ligands triggering the inflammatory response regulation: a link to brain pathology. Pharmacol. Rep. 73, 1004–1019. doi: 10.1007/s43440-021-00271-x, PMID: PubMed DOI PMC

Vallières N., Berard J. L., David S., Lacroix S. (2006). Systemic injections of lipopolysaccharide accelerates myelin phagocytosis during Wallerian degeneration in the injured mouse spinal cord. Glia 53, 103–113. doi: 10.1002/glia.20266, PMID: PubMed DOI

van Lieshout J. H., Dibué-Adjei M., Cornelius J. F., Slotty P. J., Schneider T., Restin T., et al. . (2018). An introduction to the pathophysiology of aneurysmal subarachnoid hemorrhage. Neurosurg. Rev. 41, 917–930. doi: 10.1007/s10143-017-0827-y, PMID: PubMed DOI

Veelken J. A., Laing R. J., Jakubowski J. (1995). The Sheffield model of subarachnoid hemorrhage in rats. Stroke 26, 1279–1284. doi: 10.1161/01.str.26.7.1279, PMID: PubMed DOI

Wan Y., Hua Y., Garton H. J. L., Novakovic N., Keep R. F., Xi G. (2019). Activation of epiplexus macrophages in hydrocephalus caused by subarachnoid hemorrhage and thrombin. CNS Neurosci. Ther. 25, 1134–1141. doi: 10.1111/cns.13203, PMID: PubMed DOI PMC

Wei J., Dai S., Pu C., Luo P., Yang Y., Jiang X., et al. . (2022). Protective role of TLR9-induced macrophage/microglia phagocytosis after experimental intracerebral hemorrhage in mice. CNS Neurosci. Ther. 28, 1800–1813. doi: 10.1111/cns.13919, PMID: PubMed DOI PMC

Wei C., Guo S., Liu W., Jin F., Wei B., Fan H., et al. . (2020). Resolvin D1 ameliorates inflammation-mediated blood-brain barrier disruption after subarachnoid hemorrhage in rats by modulating A20 and NLRP3 Inflammasome. Front. Pharmacol. 11:610734. doi: 10.3389/fphar.2020.610734, PMID: PubMed DOI PMC

Wenceslau C. F., Szasz T., McCarthy C. G., Baban B., NeSmith E., Webb R. C. (2016). Mitochondrial N-formyl peptides cause airway contraction and lung neutrophil infiltration via formyl peptide receptor activation. Pulm. Pharmacol. Ther. 37, 49–56. doi: 10.1016/j.pupt.2016.02.005, PMID: PubMed DOI PMC

Wilson E. H., Weninger W., Hunter C. A. (2010). Trafficking of immune cells in the central nervous system. J. Clin. Invest. 120, 1368–1379. doi: 10.1172/JCI41911, PMID: PubMed DOI PMC

Wolburg H., Paulus W. (2010). Choroid plexus: biology and pathology. Acta Neuropathol. 119, 75–88. doi: 10.1007/s00401-009-0627-8 PubMed DOI

Wu T.-T., Chen T.-L., Chen R.-M. (2009). Lipopolysaccharide triggers macrophage activation of inflammatory cytokine expression, chemotaxis, phagocytosis, and oxidative ability via a toll-like receptor 4-dependent pathway: validated by RNA interference. Toxicol. Lett. 191, 195–202. doi: 10.1016/j.toxlet.2009.08.025, PMID: PubMed DOI

Xiang J., Routhe L. J., Andrew Wilkinson D., Hua Y., Moos T., Xi G., et al. . (2017). The choroid plexus as a site of damage in hemorrhagic and ischemic stroke and its role in responding to injury. Fluids Barriers CNS 14:8. doi: 10.1186/s12987-017-0056-3, PMID: PubMed DOI PMC

Yuan J., Lin F., Chen L., Chen W., Pan X., Bai Y., et al. . (2022). Lipoxin A4 regulates M1/M2 macrophage polarization via FPR2-IRF pathway. Inflammopharmacology 30, 487–498. doi: 10.1007/s10787-022-00942-y, PMID: PubMed DOI

Zamboni L. (1967). Buffered picric acid-formaldehyde: A new rapid fixation for electron microscopy. J. Cell Biol. 35:148A. Available at: https://cir.nii.ac.jp/crid/1571135650533875968 (Accessed July 12, 2022).

Zhang Q., Raoof M., Chen Y., Sumi Y., Sursal T., Junger W., et al. . (2010). Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107. doi: 10.1038/nature08780, PMID: PubMed DOI PMC

Zhang Z., Zhang A., Liu Y., Hu X., Fang Y., Wang X., et al. . (2022). New mechanisms and targets of subarachnoid hemorrhage: A focus on mitochondria. Curr. Neuropharmacol. 20, 1278–1296. doi: 10.2174/1570159X19666211101103646, PMID: PubMed DOI PMC

Zhao B. N., Campbell J. J., Salanga C. L., Ertl L. S., Wang Y., Yau S., et al. . (2019). CCR2-mediated uptake of constitutively produced CCL2: A mechanism for regulating chemokine levels in the blood. J. Immunol. 203, 3157–3165. doi: 10.4049/jimmunol.1900961, PMID: PubMed DOI PMC