Aurora Semerano, MD
@semerano_aurora
Age is the most important non-modifiable stroke risk factor. Over 80% of ischemic strokes occur in people aged 65 years and older. Elderly patients with stroke have higher mortality, greater disability, and longer hospitalizations, they receive less evidence-based care, and they are less likely to be discharged to their original place of residence.1 Understanding the mechanisms of increased vulnerability that occurs with age is pivotal to reveal new therapeutic opportunities for stroke.
A profound dysregulation of the immune system is observed in elderly people, and it is commonly referred to with the term “inflamm-ageing”,2 characterized by a persistent subtle increase of inflammatory stress accompanied by a blunted inflammatory response to immunogenic triggers. “Inflamm-ageing” likely contributes to the pathophysiology of different age-dependent conditions, including stroke. Patients with ischemic stroke showed increased plasma levels of the pro-inflammatory cytokine TNF-α with age.3 A transcriptomic analysis of peripheral blood RNA in patients with acute ischemic stroke revealed differential expression in aged and young patients, mostly in genes associated with altered B-cell receptor signaling, lymphocyte proliferation, and leukocyte homeostasis.4 In human postmortem brain tissue, age positively correlates with neutrophil infiltration, MMP-9 expression, and hemorrhagic transformation.5 However, studying ageing and its consequences in humans is tricky as other cerebrovascular risk factors can operate as confounders. In this context, experimental stroke in rodents offers the advantage to isolate the effects of ageing. TNF-α inhibition restored the volume of cerebral infarct, neuromotor performance, and survival rates in aged stroke mice to the levels observed in young ones.3 After middle cerebral artery occlusion (MCAO), aged animals reconstituted with young bone marrow showed reduced behavioral deficits and significantly fewer brain-infiltrating neutrophils compared to younger controls.5
Wang et al. previously6 showed that small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) can induce ischemic neuroprotection in mice, mostly by reducing the brain infiltration of neutrophils. In their new publication7 in Stroke, the same authors aimed at examining the immunomodulant effects of sEVs in stroke of the aged. They compared the effects of MSC-sEVs (raised from healthy human bone marrow) in young and aged mice exposed to 30-minutes MCAO. According to the experimental design, MSC-sEVs were intravenously administered immediately after reperfusion or with 6 hours delay, and both brain and peripheral blood leukocytes were evaluated via flow cytometry. MSC-sEV administration very similarly resulted in better neurological conditions, reduced infarct volume, and less injured neurons in young and aged mice. Interestingly, in aged mice, decreased brain edema and ICAM-1 abundance were also observed, which was not significant in young animals. When analyzing post-ischemic infiltration of the CNS, total leukocytes, neutrophils, monocytes, and macrophages were reduced by MSC-sEVs in ischemic brain of aged mice. Peripheral blood profiles at 3 days post-ischemia were remarkably different in vehicle-treated young and aged mice, confirming the age-dependent phenotypic shift from lymphoid to myeloid lineage: Indeed, aged mice had increased circulating polymorphonuclear leukocytes, as well as lower counts of lymphocytes; moreover, they displayed less macrophages and patrolling monocytes in the blood. MSCs-sEV administration did not reverse postischemic lymphopenia (at least at 3 days), nor affected the neutrophil counts, but resulted in decreased blood monocytes and activated T cells in aged mice.
The present and the previous studies about the immunomodulant role of sEVs in cerebral ischemia open to promising perspectives for clinical translation in stroke: Whereas the neuroprotective effects seem to be mostly driven by the reduced infiltration of neutrophils in the ischemic brain, it is remarkable that sEV administration does not significantly affect neutrophil counts and activation in the peripheral blood. This might be clinically significant, considering that anti-neutrophil depletive approaches might turn to be detrimental due to the risk of serious infections that may potentially affect the final outcome, especially in elderly patients.8 Whereas the mechanisms that underlie these findings need to be further explored, the present study adds an important step toward a clinically relevant science, encouraging proper refinements of experimental design (i.e., by using aged and female animal models) for advancing stroke research.
References:
1 Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al.; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation. 2020 3;141(9):e139-e596.
2Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244-54.
3Liberale L, Bonetti NR, Puspitasari YM, Vukolic A, Akhmedov A, Diaz-Cañestro C, et al. TNF-α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm-ageing. Eur J Clin Invest. 2021;51(11):e13600.
4Sykes GP, Kamtchum-Tatuene J, Falcione S, Zehnder S, Munsterman D, Stamova B, et al. Aging Immune System in Acute Ischemic Stroke: A Transcriptomic Analysis. Stroke. 2021;52(4):1355-1361.
5Ritzel RM, Lai YJ, Crapser JD, Patel AR, Schrecengost A, Grenier JM, et al. Aging alters the immunological response to ischemic stroke. Acta Neuropathol. 2018;136(1):89-110.
6Wang C, Börger V, Sardari M, Murke F, Skuljec J, Pul R, Hagemann N, Dzyubenko E, Dittrich R, Gregorius J, Hasenberg M, Kleinschnitz C, Popa-Wagner A, Doeppner TR, Gunzer M, Giebel B, Hermann DM. Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles Induce Ischemic Neuroprotection by Modulating Leukocytes and Specifically Neutrophils. Stroke. 2020;51(6):1825-1834.
7Wang C, Börger V, Mohamud Yusuf A, Tertel T, Stambouli O, Murke F, et al. Postischemic Neuroprotection Associated With Anti-Inflammatory Effects by Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles in Aged Mice. Stroke. 2021 Dec 1:STROKEAHA121035821.
8Jickling GC, Liu D, Ander BP, Stamova B, Zhan X, Sharp FR. Targeting neutrophils in ischemic stroke: translational insights from experimental studies. J Cereb Blood Flow Metab. 2015;35(6):888-901.
