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image of Exploring the Causal Relationships and Underlying Mechanisms of Genetically Linked Immune Cells with Hemorrhagic Stroke

Abstract

Introduction

Hemorrhagic stroke is a severe disease that endangers human life and well-being, with unclear pathogenesis. Recent studies have found an association between the immune system and hemorrhagic stroke, but the causal relationship between them remains unclear. We aim to elucidate the causal relationships between immune cell traits and hemorrhagic stroke using Mendelian randomization (MR).

Methods

We collected genome-wide association studies (GWAS) summary statistics for 731 immune cell traits as exposures, and GWAS data for hemorrhagic stroke outcomes, including intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and cerebral aneurysm (non-ruptured) (CA), from the FinnGen Consortium's R10 dataset. Five methods were employed to evaluate the causal relationships, with the primary method being the inverse-variance weighted (IVW) method. Sensitivity analyses were carried out to enhance the robustness. Subsequently, we performed multivariate MR analyses, including confounding variables. Additionally, reverse MR analyses were carried out. Ultimately, we conducted pathway and functional enrichment analyses.

Results

After univariate and multivariate MR analyses, we identified that the higher counts of herpesvirus entry mediator (HVEM) on effector memory (EM) CD4+ cells (OR=0.954, 95%CI:0.925-0.984, =0.003, =0.120) were a protective factor for SAH, and the counts of forward scatter area (FSC-A) on plasmacytoid dendritic cells (DC) (OR=1.059, 95%CI:1.023-1.095, =0.001, =0.066) were associated with an increased risk of CA. The reverse MR indicated that CA could significantly increase the effector memory (EM) DN (CD4-CD8-) AC counts. No significant pleiotropy or heterogeneity was calculated in the MR analyses. SNP annotation and enrichment analyses suggested possible mechanisms by which immune cells affect hemorrhagic stroke.

Discussion

The involvement of immune cells in the neuroinflammatory responses has been demonstrated in previous studies. Among the immune cell traits with a significant causal relationship to hemorrhagic stroke, higher levels of HVEM on EM CD4+ cells may inhibit further inflammatory progress by binding to corresponding receptors, thereby exerting a protective effect against SAH. Alterations in FSC-A values (a flow cytometry measure of cell size) of plasmacytoid dendritic cells may contribute to atherosclerosis through cascading reactions that ultimately lead to CA. In addition, based on existing studies, other immune cell traits and related pathways identified in this study may contribute to the prevention and treatment of hemorrhagic stroke, providing a reference for future research. Finally, this study has some limitations, including population specificity, the use of a relatively lenient significance threshold ( < 1 × 10-5), and potential bias from weak instrumental variables and pleiotropy.

Conclusion

This study demonstrated the causal relationships between immune cell traits and hemorrhagic stroke, laying the foundation for understanding the underlying mechanisms.

© 2025 Bentham Science Publishers
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2025-08-11
2025-09-05

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References

  1. Xu Y. Chen A. Wu J. Wan Y. You M. Gu X. Guo H. Tan S. He Q. Hu B. Nanomedicine: An emerging novel therapeutic strategy for hemorrhagic stroke. Int. J. Nanomedicine 2022 17 1927 1950 10.2147/IJN.S357598 35530973
    [Google Scholar]
  2. Broderick J.P. Grotta J.C. Naidech A.M. Steiner T. Sprigg N. Toyoda K. Dowlatshahi D. Demchuk A.M. Selim M. Mocco J. Mayer S. The story of intracerebral hemorrhage. Stroke 2021 52 5 1905 1914 10.1161/STROKEAHA.121.033484 33827245
    [Google Scholar]
  3. Lawton M.T. Vates G.E. Subarachnoid hemorrhage. N. Engl. J. Med. 2017 377 3 257 266 10.1056/NEJMcp1605827 28723321
    [Google Scholar]
  4. Ohashi S.N. DeLong J.H. Kozberg M.G. Mazur-Hart D.J. van Veluw S.J. Alkayed N.J. Sansing L.H. Role of inflammatory processes in hemorrhagic stroke. Stroke 2023 54 2 605 619 10.1161/STROKEAHA.122.037155 36601948
    [Google Scholar]
  5. Feigin V.L. Stark B.A. Johnson C.O. Roth G.A. Bisignano C. Abady G.G. Abbasifard M. Abbasi-Kangevari M. Abd-Allah F. Abedi V. Abualhasan A. Abu-Rmeileh N.M.E. Abushouk A.I. Adebayo O.M. Agarwal G. Agasthi P. Ahinkorah B.O. Ahmad S. Ahmadi S. Ahmed Salih Y. Aji B. Akbarpour S. Akinyemi R.O. Al Hamad H. Alahdab F. Alif S.M. Alipour V. Aljunid S.M. Almustanyir S. Al-Raddadi R.M. Al-Shahi Salman R. Alvis-Guzman N. Ancuceanu R. Anderlini D. Anderson J.A. Ansar A. Antonazzo I.C. Arabloo J. Ärnlöv J. Artanti K.D. Aryan Z. Asgari S. Ashraf T. Athar M. Atreya A. Ausloos M. Baig A.A. Baltatu O.C. Banach M. Barboza M.A. Barker-Collo S.L. Bärnighausen T.W. Barone M.T.U. Basu S. Bazmandegan G. Beghi E. Beheshti M. Béjot Y. Bell A.W. Bennett D.A. Bensenor I.M. Bezabhe W.M. Bezabih Y.M. Bhagavathula A.S. Bhardwaj P. Bhattacharyya K. Bijani A. Bikbov B. Birhanu M.M. Boloor A. Bonny A. Brauer M. Brenner H. Bryazka D. Butt Z.A. Caetano dos Santos F.L. Campos-Nonato I.R. Cantu-Brito C. Carrero J.J. Castañeda-Orjuela C.A. Catapano A.L. Chakraborty P.A. Charan J. Choudhari S.G. Chowdhury E.K. Chu D-T. Chung S-C. Colozza D. Costa V.M. Costanzo S. Criqui M.H. Dadras O. Dagnew B. Dai X. Dalal K. Damasceno A.A.M. D’Amico E. Dandona L. Dandona R. Darega Gela J. Davletov K. De la Cruz-Góngora V. Desai R. Dhamnetiya D. Dharmaratne S.D. Dhimal M.L. Dhimal M. Diaz D. Dichgans M. Dokova K. Doshi R. Douiri A. Duncan B.B. Eftekharzadeh S. Ekholuenetale M. El Nahas N. Elgendy I.Y. Elhadi M. El-Jaafary S.I. Endres M. Endries A.Y. Erku D.A. Faraon E.J.A. Farooque U. Farzadfar F. Feroze A.H. Filip I. Fischer F. Flood D. Gad M.M. Gaidhane S. Ghanei Gheshlagh R. Ghashghaee A. Ghith N. Ghozali G. Ghozy S. Gialluisi A. Giampaoli S. Gilani S.A. Gill P.S. Gnedovskaya E.V. Golechha M. Goulart A.C. Guo Y. Gupta R. Gupta V.B. Gupta V.K. Gyanwali P. Hafezi-Nejad N. Hamidi S. Hanif A. Hankey G.J. Hargono A. Hashi A. Hassan T.S. Hassen H.Y. Havmoeller R.J. Hay S.I. Hayat K. Hegazy M.I. Herteliu C. Holla R. Hostiuc S. Househ M. Huang J. Humayun A. Hwang B-F. Iacoviello L. Iavicoli I. Ibitoye S.E. Ilesanmi O.S. Ilic I.M. Ilic M.D. Iqbal U. Irvani S.S.N. Islam S.M.S. Ismail N.E. Iso H. Isola G. Iwagami M. Jacob L. Jain V. Jang S-I. Jayapal S.K. Jayaram S. Jayawardena R. Jeemon P. Jha R.P. Johnson W.D. Jonas J.B. Joseph N. Jozwiak J.J. Jürisson M. Kalani R. Kalhor R. Kalkonde Y. Kamath A. Kamiab Z. Kanchan T. Kandel H. Karch A. Katoto P.D.M.C. Kayode G.A. Keshavarz P. Khader Y.S. Khan E.A. Khan I.A. Khan M. Khan M.A.B. Khatib M.N. Khubchandani J. Kim G.R. Kim M.S. Kim Y.J. Kisa A. Kisa S. Kivimäki M. Kolte D. Koolivand A. Koulmane Laxminarayana S.L. Koyanagi A. Krishan K. Krishnamoorthy V. Krishnamurthi R.V. Kumar G.A. Kusuma D. La Vecchia C. Lacey B. Lak H.M. Lallukka T. Lasrado S. Lavados P.M. Leonardi M. Li B. Li S. Lin H. Lin R-T. Liu X. Lo W.D. Lorkowski S. Lucchetti G. Lutzky Saute R. Magdy Abd El Razek H. Magnani F.G. Mahajan P.B. Majeed A. Makki A. Malekzadeh R. Malik A.A. Manafi N. Mansournia M.A. Mantovani L.G. Martini S. Mazzaglia G. Mehndiratta M.M. Menezes R.G. Meretoja A. Mersha A.G. Miao Jonasson J. Miazgowski B. Miazgowski T. Michalek I.M. Mirrakhimov E.M. Mohammad Y. Mohammadian-Hafshejani A. Mohammed S. Mokdad A.H. Mokhayeri Y. Molokhia M. Moni M.A. Montasir A.A. Moradzadeh R. Morawska L. Morze J. Muruet W. Musa K.I. Nagarajan A.J. Naghavi M. Narasimha Swamy S. Nascimento B.R. Negoi R.I. Neupane Kandel S. Nguyen T.H. Norrving B. Noubiap J.J. Nwatah V.E. Oancea B. Odukoya O.O. Olagunju A.T. Orru H. Owolabi M.O. Padubidri J.R. Pana A. Parekh T. Park E-C. Pashazadeh Kan F. Pathak M. Peres M.F.P. Perianayagam A. Pham T-M. Piradov M.A. Podder V. Polinder S. Postma M.J. Pourshams A. Radfar A. Rafiei A. Raggi A. Rahim F. Rahimi-Movaghar V. Rahman M. Rahman M.A. Rahmani A.M. Rajai N. Ranasinghe P. Rao C.R. Rao S.J. Rathi P. Rawaf D.L. Rawaf S. Reitsma M.B. Renjith V. Renzaho A.M.N. Rezapour A. Rodriguez J.A.B. Roever L. Romoli M. Rynkiewicz A. Sacco S. Sadeghi M. Saeedi Moghaddam S. Sahebkar A. Saif-Ur-Rahman K.M. Salah R. Samaei M. Samy A.M. Santos I.S. Santric-Milicevic M.M. Sarrafzadegan N. Sathian B. Sattin D. Schiavolin S. Schlaich M.P. Schmidt M.I. Schutte A.E. Sepanlou S.G. Seylani A. Sha F. Shahabi S. Shaikh M.A. Shannawaz M. Shawon M.S.R. Sheikh A. Sheikhbahaei S. Shibuya K. Siabani S. Silva D.A.S. Singh J.A. Singh J.K. Skryabin V.Y. Skryabina A.A. Sobaih B.H. Stortecky S. Stranges S. Tadesse E.G. Tarigan I.U. Temsah M-H. Teuschl Y. Thrift A.G. Tonelli M. Tovani-Palone M.R. Tran B.X. Tripathi M. Tsegaye G.W. Ullah A. Unim B. Unnikrishnan B. Vakilian A. Valadan Tahbaz S. Vasankari T.J. Venketasubramanian N. Vervoort D. Vo B. Volovici V. Vosoughi K. Vu G.T. Vu L.G. Wafa H.A. Waheed Y. Wang Y. Wijeratne T. Winkler A.S. Wolfe C.D.A. Woodward M. Wu J.H. Wulf Hanson S. Xu X. Yadav L. Yadollahpour A. Yahyazadeh Jabbari S.H. Yamagishi K. Yatsuya H. Yonemoto N. Yu C. Yunusa I. Zaman M.S. Zaman S.B. Zamanian M. Zand R. Zandifar A. Zastrozhin M.S. Zastrozhina A. Zhang Y. Zhang Z-J. Zhong C. Zuniga Y.M.H. Murray C.J.L. GBD 2019 Stroke Collaborators 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 Neurol. 2021 20 10 795 820 10.1016/S1474‑4422(21)00252‑0 34487721
    [Google Scholar]
  6. Owolabi M.O. Thrift A.G. Mahal A. Ishida M. Martins S. Johnson W.D. Pandian J. Abd-Allah F. Yaria J. Phan H.T. Roth G. Gall S.L. Beare R. Phan T.G. Mikulik R. Akinyemi R.O. Norrving B. Brainin M. Feigin V.L. Abanto C. Abera S.F. Addissie A. Adebayo O. Adeleye A.O. Adilbekov Y. Adilbekova B. Adoukonou T.A. Aguiar de Sousa D. Ajagbe T. Akhmetzhanova Z. Akpalu A. Álvarez Ahlgren J. Ameriso S. Andonova S. Awoniyi F.E. Bakhiet M. Barboza M. Basri H. Bath P. Bello O. Bereczki D. Beretta S. Berkowitz A. Bernabé-Ortiz A. Bernhardt J. Berzina G. Bisharyan M. Bovet P. Budincevic H. Cadilhac D. Caso V. Chen C. Chin J. Chwojnicki K. Conforto A. Cruz V.T. D’Amelio M. Danielyan K. Davis S. Demarin V. Dempsey R. Dichgans M. Dokova K. Donnan G. Elkind M.S. Endres M. Fischer U. Gankpé F. Gaye Saavedra A. Gil A. Giroud M. Gnedovskaya E. Hachinski V. Hafdi M. Hamadeh R. Hamzat T.K. Hankey G. Heldner M. Ibrahim E.A. Ibrahim N.M. Inoue M. Jee S. Jeng J-S. Kalkonde Y. Kamenova S. Karaszewski B. Kelly P. Khan T. Kiechl S. Kondybayeva A. Kõrv J. Kravchenko M. Krishnamurthi R.V. Kruja J. Lakkhanaloet M. Langhorne P. Lavados P.M. Law Z.K. Lawal A. Lazo-Porras M. Lebedynets D. Lee T-H. Leung T. Liebeskind D.S. Lindsay P. López-Jaramillo P. Lotufo P.A. Machline-Carrion J. Makanjuola A. Markus H.S. Marquez-Romero J.M. Medina M. Medukhanova S. Mehndiratta M.M. Merkin A. Mirrakhimov E. Mohl S. Moscoso-Porras M. Müller-Stierlin A. Murphy S. Musa K.I. Nasreldein A. Nogueira R.G. Nolte C. Noubiap J.J. Novarro-Escudero N. Ogun Y. Oguntoye R.A. Oraby M.I. Osundina M. Ovbiagele B. Orken D.N. Ozdemir A.Ö. Ozturk S. Paccot M. Phromjai J. Piradov P. Platz T. Potpara T. Ranta A. Rathore F. Richard E. Sacco R.L. Sahathevan R. Santos Carquín I. Saposnik G. Sarfo F.S. Sharma M. Sheth K. Shobhana A. Suwanwela N. Svyato I. Sylaja P.N. Tao X. Thakur K.T. Toni D. Topcuoglu M.A. Torales J. Towfighi A. Truelsen T.C. Tsiskaridze A. Tulloch-Reid M. Useche N. Vanacker P. Vassilopoulou S. Vukorepa G. Vuletic V. Wahab K.W. Wang W. Wijeratne T. Wolfe C. Yifru Y.M. Yock-Corrales A. Yonemoto N. Yperzeele L. Zhang P. Stroke Experts Collaboration Group Primary stroke prevention worldwide: Translating evidence into action. Lancet Public Health 2022 7 1 e74 e85 10.1016/S2468‑2667(21)00230‑9 34756176
    [Google Scholar]
  7. Alsbrook D.L. Di Napoli M. Bhatia K. Biller J. Andalib S. Hinduja A. Rodrigues R. Rodriguez M. Sabbagh S.Y. Selim M. Farahabadi M.H. Jafarli A. Divani A.A. Neuroinflammation in acute ischemic and hemorrhagic stroke. Curr. Neurol. Neurosci. Rep. 2023 23 8 407 431 10.1007/s11910‑023‑01282‑2 37395873
    [Google Scholar]
  8. Daëron M. The immune system as a system of relations. Front. Immunol. 2022 13 984678 10.3389/fimmu.2022.984678 36177051
    [Google Scholar]
  9. Malone K. Amu S. Moore A.C. Waeber C. The immune system and stroke: From current targets to future therapy. Immunol. Cell Biol. 2019 97 1 5 16 10.1111/imcb.12191 30022515
    [Google Scholar]
  10. Jiang C. Wang Y. Hu Q. Shou J. Zhu L. Tian N. Sun L. Luo H. Zuo F. Li F. Wang Y. Zhang J. Wang J. Wang J. Zhang J. Immune changes in peripheral blood and hematoma of patients with intracerebral hemorrhage. FASEB J. 2020 34 2 2774 2791 10.1096/fj.201902478R 31912591
    [Google Scholar]
  11. Zeyu Zhang Yuanjian Fang Cameron Lenahan Sheng Chen The role of immune inflammation in aneurysmal subarachnoid hemorrhage. Exp. Neurol. 2021 336 113535 10.1016/j.expneurol.2020.113535 33249033
    [Google Scholar]
  12. Zhao Z. Pan Z. Zhang S. Ma G. Zhang W. Song J. Wang Y. Kong L. Du G. Neutrophil extracellular traps: A novel target for the treatment of stroke. Pharmacol. Ther. 2023 241 108328 10.1016/j.pharmthera.2022.108328 36481433
    [Google Scholar]
  13. Iadecola C. Buckwalter M.S. Anrather J. Immune responses to stroke: Mechanisms, modulation, and therapeutic potential. J. Clin. Invest. 2020 130 6 2777 2788 10.1172/JCI135530 32391806
    [Google Scholar]
  14. Zhang B.W. Sun K.H. Liu T. Zou W. The crosstalk between immune cells after intracerebral hemorrhage. Neuroscience 2024 537 93 104 10.1016/j.neuroscience.2023.11.015 38056621
    [Google Scholar]
  15. Larsson S.C. Butterworth A.S. Burgess S. Mendelian randomization for cardiovascular diseases: Principles and applications. Eur. Heart J. 2023 44 47 4913 4924 10.1093/eurheartj/ehad736 37935836
    [Google Scholar]
  16. Ference B.A. Holmes M.V. Smith G.D. Using mendelian randomization to improve the design of randomized trials. Cold Spring Harb. Perspect. Med. 2021 11 7 a040980 10.1101/cshperspect.a040980 33431510
    [Google Scholar]
  17. de Leeuw C. Savage J. Bucur I.G. Heskes T. Posthuma D. Understanding the assumptions underlying Mendelian randomization. Eur. J. Hum. Genet. 2022 30 6 653 660 10.1038/s41431‑022‑01038‑5 35082398
    [Google Scholar]
  18. Skrivankova V.W. Richmond R.C. Woolf B.A.R. Yarmolinsky J. Davies N.M. Swanson S.A. VanderWeele T.J. Higgins J.P.T. Timpson N.J. Dimou N. Langenberg C. Golub R.M. Loder E.W. Gallo V. Tybjaerg-Hansen A. Davey Smith G. Egger M. Richards J.B. Strengthening the reporting of observational studies in epidemiology using mendelian randomization. JAMA 2021 326 16 1614 1621 10.1001/jama.2021.18236 34698778
    [Google Scholar]
  19. Orrù V. Steri M. Sidore C. Marongiu M. Serra V. Olla S. Sole G. Lai S. Dei M. Mulas A. Virdis F. Piras M.G. Lobina M. Marongiu M. Pitzalis M. Deidda F. Loizedda A. Onano S. Zoledziewska M. Sawcer S. Devoto M. Gorospe M. Abecasis G.R. Floris M. Pala M. Schlessinger D. Fiorillo E. Cucca F. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat. Genet. 2020 52 10 1036 1045 10.1038/s41588‑020‑0684‑4 32929287
    [Google Scholar]
  20. Shen Y. Liu H. Meng X. Gao A. Liu Y. Ma W. Liang H. Hu F. The causal effects between gut microbiota and hemorrhagic stroke: A bidirectional two-sample Mendelian randomization study. Front. Microbiol. 2023 14 1290909 10.3389/fmicb.2023.1290909 38188561
    [Google Scholar]
  21. Zhang X. Zhu X. Shi Q. The plasma lipids with different fatty acid chains are associated with the risk of hemorrhagic stroke: A Mendelian randomization study. Front. Neurol. 2024 15 1432878 10.3389/fneur.2024.1432878 39139767
    [Google Scholar]
  22. Cao R.R. Yu X.H. Xiong M.F. Li X.T. Deng F.Y. Lei S.F. The immune factors have complex causal regulation effects on bone mineral density. Front. Immunol. 2022 13 959417 10.3389/fimmu.2022.959417 36341399
    [Google Scholar]
  23. Han X. Wang J. Su X. Guo X. Ye H. Exploring the causal influence of 731 immune cells on 4 different glaucoma subtypes using a two-sample mendelian randomization method. Sci. Rep. 2025 15 1 5987 10.1038/s41598‑025‑90545‑8 39966504
    [Google Scholar]
  24. Li P. Wang H. Guo L. Gou X. Chen G. Lin D. Fan D. Guo X. Liu Z. Association between gut microbiota and preeclampsia-eclampsia: A two-sample Mendelian randomization study. BMC Med. 2022 20 1 443 10.1186/s12916‑022‑02657‑x 36380372
    [Google Scholar]
  25. Burgess S. Thompson S.G. CRP CHD Genetics Collaboration Avoiding bias from weak instruments in Mendelian randomization studies. Int. J. Epidemiol. 2011 40 3 755 764 10.1093/ije/dyr036 21414999
    [Google Scholar]
  26. Hemani G. Zheng J. Elsworth B. Wade K.H. Haberland V. Baird D. Laurin C. Burgess S. Bowden J. Langdon R. Tan V.Y. Yarmolinsky J. Shihab H.A. Timpson N.J. Evans D.M. Relton C. Martin R.M. Davey Smith G. Gaunt T.R. Haycock P.C. The MR-Base platform supports systematic causal inference across the human phenome. eLife 2018 7 e34408 10.7554/eLife.34408 29846171
    [Google Scholar]
  27. Ran B. Qin J. Wu Y. Wen F. Causal role of immune cells in chronic obstructive pulmonary disease: Mendelian randomization study. Expert Rev. Clin. Immunol. 2024 20 4 413 421 10.1080/1744666X.2023.2295987 38108202
    [Google Scholar]
  28. Burgess S. Bowden J. Fall T. Ingelsson E. Thompson S.G. Sensitivity analyses for robust causal inference from mendelian randomization analyses with multiple genetic variants. Epidemiology 2017 28 1 30 42 10.1097/EDE.0000000000000559 27749700
    [Google Scholar]
  29. Ye X. Liu B. Bai Y. Cao Y. Lin S. Lyu L. Meng H. Dai Y. Ye D. Pan W. Wang Z. Mao Y. Chen Q. Genetic evidence strengthens the bidirectional connection between gut microbiota and periodontitis: Insights from a two-sample Mendelian randomization study. J. Transl. Med. 2023 21 1 674 10.1186/s12967‑023‑04559‑9 37770955
    [Google Scholar]
  30. Burgess S. Davey Smith G. Davies N.M. Dudbridge F. Gill D. Glymour M.M. Hartwig F.P. Kutalik Z. Holmes M.V. Minelli C. Morrison J.V. Pan W. Relton C.L. Theodoratou E. Guidelines for performing Mendelian randomization investigations: Update for summer 2023. Wellcome Open Res. 2019 4 186 10.12688/wellcomeopenres.15555.3 32760811
    [Google Scholar]
  31. Chen X. Kong J. Diao X. Cai J. Zheng J. Xie W. Qin H. Huang J. Lin T. Depression and prostate cancer risk: A Mendelian randomization study. Cancer Med. 2020 9 23 9160 9167 10.1002/cam4.3493 33027558
    [Google Scholar]
  32. Kolberg L. Raudvere U. Kuzmin I. Adler P. Vilo J. Peterson H. g:Profiler—interoperable web service for functional enrichment analysis and gene identifier mapping (2023 update). Nucleic Acids Res. 2023 51 W1 W207 W212 10.1093/nar/gkad347 37144459
    [Google Scholar]
  33. Ma Y. Yang S. He Q. Zhang D. Chang J. The role of immune cells in post-stroke angiogenesis and neuronal remodeling: The known and the unknown. Front. Immunol. 2021 12 784098 10.3389/fimmu.2021.784098 34975872
    [Google Scholar]
  34. Li X. Chen G. CNS-peripheral immune interactions in hemorrhagic stroke. J. Cereb. Blood Flow Metab. 2023 43 2 185 197 10.1177/0271678X221145089 36476130
    [Google Scholar]
  35. Chen S. Li L. Peng C. Bian C. Ocak P.E. Zhang J.H. Yang Y. Zhou D. Chen G. Luo Y. Targeting oxidative stress and inflammatory response for blood–brain barrier protection in intracerebral hemorrhage. Antioxid. Redox Signal. 2022 37 1-3 115 134 10.1089/ars.2021.0072 35383484
    [Google Scholar]
  36. Guo Y. Dai W. Zheng Y. Qiao W. Chen W. Peng L. Zhou H. Zhao T. Liu H. Zheng F. Sun P. Mechanism and regulation of microglia polarization in intracerebral hemorrhage. Molecules 2022 27 20 7080 10.3390/molecules27207080 36296682
    [Google Scholar]
  37. Dong H. Wen X. Zhang B.W. Wu Z. Zou W. Astrocytes in intracerebral hemorrhage: Impact and therapeutic objectives. Front. Mol. Neurosci. 2024 17 1327472 10.3389/fnmol.2024.1327472 38419793
    [Google Scholar]
  38. Lee T.H. Liu P.S. Tsai M.M. Chen J.L. Wang S.J. Hsieh H.L. The COX-2-derived PGE2 autocrine contributes to bradykinin-induced matrix metalloproteinase-9 expression and astrocytic migration via STAT3 signaling. Cell Commun. Signal. 2020 18 1 185 10.1186/s12964‑020‑00680‑0 33228717
    [Google Scholar]
  39. Tschoe C. Bushnell C.D. Duncan P.W. Alexander-Miller M.A. Wolfe S.Q. Neuroinflammation after intracerebral hemorrhage and potential therapeutic targets. J. Stroke 2020 22 1 29 46 10.5853/jos.2019.02236 32027790
    [Google Scholar]
  40. Chaudhry S.R. Kahlert U.D. Kinfe T.M. Endl E. Dolf A. Niemelä M. Hänggi D. Muhammad S. Differential polarization and activation dynamics of systemic T helper cell subsets after aneurysmal subarachnoid hemorrhage (SAH) and during post-SAH complications. Sci. Rep. 2021 11 1 14226 10.1038/s41598‑021‑92873‑x 34244562
    [Google Scholar]
  41. Lauzier D.C. Athiraman U. Role of microglia after subarachnoid hemorrhage. J. Cereb. Blood Flow Metab. 2024 44 6 841 856 10.1177/0271678X241237070 38415607
    [Google Scholar]
  42. Liu Y. Chen S. Liu S. Wallace K.L. Zille M. Zhang J. Wang J. Jiang C. T-cell receptor signaling modulated by the co-receptors: Potential targets for stroke treatment. Pharmacol. Res. 2023 192 106797 10.1016/j.phrs.2023.106797 37211238
    [Google Scholar]
  43. Stanzione R. Forte M. Cotugno M. Bianchi F. Marchitti S. Rubattu S. Role of DAMPs and of leukocytes infiltration in ischemic stroke: Insights from animal models and translation to the human disease. Cell. Mol. Neurobiol. 2022 42 3 545 556 10.1007/s10571‑020‑00966‑4 32996044
    [Google Scholar]
  44. Zhang D. Ren J. Luo Y. He Q. Zhao R. Chang J. Yang Y. Guo Z.N. T cell response in ischemic stroke: From mechanisms to translational insights. Front. Immunol. 2021 12 707972 10.3389/fimmu.2021.707972 34335623
    [Google Scholar]
  45. Gong Z. Guo J. Liu B. Guo Y. Cheng C. Jiang Y. Liang N. Hu M. Song T. Yang L. Li H. Zhang H. Zong X. Che Q. Shi N. Mechanisms of immune response and cell death in ischemic stroke and their regulation by natural compounds. Front. Immunol. 2024 14 1287857 10.3389/fimmu.2023.1287857 38274789
    [Google Scholar]
  46. Rayasam A. Hsu M. Kijak J.A. Kissel L. Hernandez G. Sandor M. Fabry Z. Immune responses in stroke: how the immune system contributes to damage and healing after stroke and how this knowledge could be translated to better cures? Immunology 2018 154 3 363 376 10.1111/imm.12918 29494762
    [Google Scholar]
  47. Wang K. Zhang B. Li M. Duan H. Jiang Z. Gao S. Chen J. Fang S. Evaluation of the causal effects of immune cells on ischemic stroke: A Mendelian randomization study. Front. Immunol. 2024 15 1374350 10.3389/fimmu.2024.1374350 38855113
    [Google Scholar]
  48. Shi S.X. Xiu Y. Li Y. Yuan M. Shi K. Liu Q. Wang X. Jin W.N. CD4+ T cells aggravate hemorrhagic brain injury. Sci. Adv. 2023 9 23 eabq0712 10.1126/sciadv.abq0712 37285421
    [Google Scholar]
  49. Zhong Q. Zhou K. Liang Q.L. Lin S. Wang Y.C. Xiong X.Y. Meng Z.Y. Zhao T. Zhu W.Y. Yang Y.R. Liao M.F. Gong Q.W. Liu L. Xiong A. Hao J. Wang J. Yang Q.W. Interleukin‐23 secreted by activated macrophages drives γδT cell production of interleukin‐17 to aggravate secondary injury after intracerebral hemorrhage. J. Am. Heart Assoc. 2016 5 10 e004340 10.1161/JAHA.116.004340 27729335
    [Google Scholar]
  50. Ye L. Cheng H-W. Gao L. Li P-P. Shao T-Y. Mao X. Qi H. Wu B-S. Shan M. Neurotoxic role of interleukin-17 in neural stem cell differentiation after intracerebral hemorrhage. Neural Regen. Res. 2020 15 7 1350 1359 10.4103/1673‑5374.272614 31960824
    [Google Scholar]
  51. Seo G.Y. Shui J.W. Takahashi D. Song C. Wang Q. Kim K. Mikulski Z. Chandra S. Giles D.A. Zahner S. Kim P.H. Cheroutre H. Colonna M. Kronenberg M. LIGHT-HVEM signaling in innate lymphoid cell subsets protects against enteric bacterial infection. Cell Host Microbe 2018 24 2 249 260.e4 10.1016/j.chom.2018.07.008 30092201
    [Google Scholar]
  52. Liu W. Chou T.F. Garrett-Thomson S.C. Seo G.Y. Fedorov E. Ramagopal U.A. Bonanno J.B. Wang Q. Kim K. Garforth S.J. Kakugawa K. Cheroutre H. Kronenberg M. Almo S.C. HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160. J. Exp. Med. 2021 218 12 e20211112 10.1084/jem.20211112 34709351
    [Google Scholar]
  53. Yu X. Zheng Y. Mao R. Su Z. Zhang J. BTLA/HVEM signaling: Milestones in research and role in chronic hepatitis B virus infection. Front. Immunol. 2019 10 617 10.3389/fimmu.2019.00617 30984188
    [Google Scholar]
  54. Rodriguez-Barbosa J.I. Schneider P. Weigert A. Lee K.M. Kim T.J. Perez-Simon J.A. del Rio M.L. HVEM, a cosignaling molecular switch, and its interactions with BTLA, CD160 and LIGHT. Cell. Mol. Immunol. 2019 16 7 679 682 10.1038/s41423‑019‑0241‑1 31160757
    [Google Scholar]
  55. Wakeley M.E. Armstead B.E. Gray C.C. Tindal E.W. Heffernan D.S. Chung C.S. Ayala A. Lymphocyte HVEM/BTLA co-expression after critical illness demonstrates severity indiscriminate upregulation, impacting critical illness-induced immunosuppression. Front. Med. (Lausanne) 2023 10 1176602 10.3389/fmed.2023.1176602 37305124
    [Google Scholar]
  56. Salvador A.F.M. Abduljawad N. Kipnis J. Meningeal lymphatics in central nervous system diseases. Annu. Rev. Neurosci. 2024 47 1 323 344 10.1146/annurev‑neuro‑113023‑103045 38648267
    [Google Scholar]
  57. Fitzpatrick Z. Ghabdan Zanluqui N. Rosenblum J.S. Tuong Z.K. Lee C.Y.C. Chandrashekhar V. Negro-Demontel M.L. Stewart A.P. Posner D.A. Buckley M. Allinson K.S.J. Mastorakos P. Chittiboina P. Maric D. Donahue D. Helmy A. Tajsic T. Ferdinand J.R. Portet A. Peñalver A. Gillman E. Zhuang Z. Clatworthy M.R. McGavern D.B. Venous-plexus-associated lymphoid hubs support meningeal humoral immunity. Nature 2024 628 8008 612 619 10.1038/s41586‑024‑07202‑9 38509366
    [Google Scholar]
  58. Balan S. Saxena M. Bhardwaj N. Dendritic cell subsets and locations. Int. Rev. Cell Mol. Biol. 2019 348 1 68 10.1016/bs.ircmb.2019.07.004 31810551
    [Google Scholar]
  59. Tsymbalyuk O. Gerzanich V. Simard J.M. Rathinam C.V. Traumatic brain injury alters dendritic cell differentiation and distribution in lymphoid and non-lymphoid organs. J. Neuroinflammation 2022 19 1 238 10.1186/s12974‑022‑02609‑5 36183126
    [Google Scholar]
  60. Somebang K. Rudolph J. Imhof I. Li L. Niemi E.C. Shigenaga J. Tran H. Gill T.M. Lo I. Zabel B.A. Schmajuk G. Wipke B.T. Gyoneva S. Jandreski L. Craft M. Benedetto G. Plowey E.D. Charo I. Campbell J. Ye C.J. Panter S.S. Nakamura M.C. Eckalbar W. Hsieh C.L. CCR2 deficiency alters activation of microglia subsets in traumatic brain injury. Cell Rep. 2021 36 12 109727 10.1016/j.celrep.2021.109727 34551293
    [Google Scholar]
  61. Chen C. Chencheng Z. Cuiying L. Xiaokun G. Plasmacytoid dendritic cells protect against middle cerebral artery occlusion induced brain injury by priming regulatory T cells. Front. Cell. Neurosci. 2020 14 8 10.3389/fncel.2020.00008 32076400
    [Google Scholar]
  62. Ah Kioon M.D. Laurent P. Chaudhary V. Du Y. Crow M.K. Barrat F.J. Modulation of plasmacytoid dendritic cells response in inflammation and autoimmunity. Immunol. Rev. 2024 323 1 241 256 10.1111/imr.13331 38553621
    [Google Scholar]
  63. Adams N.M. Das A. Yun T.J. Reizis B. Ontogeny and Function of Plasmacytoid Dendritic Cells. Annu. Rev. Immunol. 2024 42 1 347 373 10.1146/annurev‑immunol‑090122‑041105 38941603
    [Google Scholar]
  64. Frishberg A. Kooistra E. Nuesch-Germano M. Pecht T. Milman N. Reusch N. Warnat-Herresthal S. Bruse N. Händler K. Theis H. Kraut M. van Rijssen E. van Cranenbroek B. Koenen H.J.P.M. Heesakkers H. van den Boogaard M. Zegers M. Pickkers P. Becker M. Aschenbrenner A.C. Ulas T. Theis F.J. Shen-Orr S.S. Schultze J.L. Kox M. Mature neutrophils and a NF-κB-to-IFN transition determine the unifying disease recovery dynamics in COVID-19. Cell Rep. Med. 2022 3 6 100652 10.1016/j.xcrm.2022.100652 35675822
    [Google Scholar]
  65. Sage A.P. Murphy D. Maffia P. Masters L.M. Sabir S.R. Baker L.L. Cambrook H. Finigan A.J. Ait-Oufella H. Grassia G. Harrison J.E. Ludewig B. Reith W. Hansson G.K. Reizis B. Hugues S. Mallat Z. MHC Class II-restricted antigen presentation by plasmacytoid dendritic cells drives proatherogenic T cell immunity. Circulation 2014 130 16 1363 1373 10.1161/CIRCULATIONAHA.114.011090 25223984
    [Google Scholar]
  66. Young L.J. Wilson N.S. Schnorrer P. Proietto A. ten Broeke T. Matsuki Y. Mount A.M. Belz G.T. O’Keeffe M. Ohmura-Hoshino M. Ishido S. Stoorvogel W. Heath W.R. Shortman K. Villadangos J.A. Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells. Nat. Immunol. 2008 9 11 1244 1252 10.1038/ni.1665 18849989
    [Google Scholar]
  67. Wang M. Thomson A.W. Yu F. Hazra R. Junagade A. Hu X. Regulatory T lymphocytes as a therapy for ischemic stroke. Semin. Immunopathol. 2023 45 3 329 346 10.1007/s00281‑022‑00975‑z 36469056
    [Google Scholar]
  68. Li N. Wang H. Hu C. Qie S. Liu Z. Regulatory T. Regulatory T cells for stroke recovery: A promising immune therapeutic strategy. CNS Neurosci. Ther. 2025 31 1 e70248 10.1111/cns.70248 39878387
    [Google Scholar]
  69. Zheng Y. Ren Z. Liu Y. Yan J. Chen C. He Y. Shi Y. Cheng F. Wang Q. Li C. Wang X. T cell interactions with microglia in immune-inflammatory processes of ischemic stroke. Neural Regen. Res. 2025 20 5 1277 1292 10.4103/NRR.NRR‑D‑23‑01385 39075894
    [Google Scholar]
  70. Rikhtegar R. Yousefi M. Dolati S. Kasmaei H.D. Charsouei S. Nouri M. Shakouri S.K. Stem cell‐based cell therapy for neuroprotection in stroke: A review. J. Cell. Biochem. 2019 120 6 8849 8862 10.1002/jcb.28207 30506720
    [Google Scholar]
  71. Ellis G.I. Sheppard N.C. Riley J.L. Genetic engineering of T cells for immunotherapy. Nat. Rev. Genet. 2021 22 7 427 447 10.1038/s41576‑021‑00329‑9 33603158
    [Google Scholar]
  72. Stephens R. Grainger J.R. Smith C.J. Allan S.M. Systemic innate myeloid responses to acute ischaemic and haemorrhagic stroke. Semin. Immunopathol. 2023 45 3 281 294 10.1007/s00281‑022‑00968‑y 36346451
    [Google Scholar]
  73. Cantatore F.P. Maruotti N. Corrado A. Ribatti D. Anti-angiogenic effects of biotechnological therapies in rheumatic diseases. Biologics 2017 11 123 128 29276377
    [Google Scholar]
  74. Ao LY Yan YY Zhou L Immune cells after ischemic stroke Onset: Roles, migration, and target intervention. J Mol Neurosci 2018 66 3 342 355 10.1007/s12031‑018‑1173‑4 30267340
    [Google Scholar]
  75. Wareham L.K. Baratta R.O. Del Buono B.J. Schlumpf E. Calkins D.J. Collagen in the central nervous system: Contributions to neurodegeneration and promise as a therapeutic target. Mol. Neurodegener. 2024 19 1 11 10.1186/s13024‑024‑00704‑0 38273335
    [Google Scholar]
  76. Lin W. Wang Y. Chen Y. Wang Q. Gu Z. Zhu Y. Role of calcium signaling pathway-related gene regulatory networks in ischemic stroke based on multiple WGCNA and single-cell analysis. Oxid. Med. Cell. Longev. 2021 2021 1 8060477 10.1155/2021/8060477 34987704
    [Google Scholar]
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Exploring the Causal Relationships and Underlying Mechanisms of Genetically Linked Immune Cells with Hemorrhagic Stroke
Bentham Science Publishers ; https://doi.org/10.2174/0115672026373219250730071202
/content/journals/cnr/10.2174/0115672026373219250730071202
/content/journals/cnr/10.2174/0115672026373219250730071202
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  • Article Type:     Research Article
Keywords: causal relationship ; genome-wide association studies ; Immune cells ; Mendelian randomization ; hemorrhagic stroke ; enrichment analyses

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