Remote limb conditioning (RLC), performed by intermittent interruption of blood flow to a limb, triggers endogenous tolerance mechanisms and improves stroke outcomes. The underlying mechanism for the protective effect involves a shift of circulating monocytes to a Ly6CHigh proinflammatory subset in normal metabolic conditions. The current study investigates the effect of RLC on stroke outcomes in subjects with obesity, a vascular comorbidity. Compared to lean mice, obese stroke mice displayed significantly higher circulating monocytes (monocytosis), increased CD45High monocytes/macrophages infiltration to the injured brain, worse acute outcomes, and delayed recovery. Unlike lean mice, obese mice with RLC at 2 hours post-stroke failed to shift circulating monocytes to pro-inflammatory status and nullified RLC-induced functional benefit. The absence of the monocyte shift was also observed in splenocytes incubated with RLC serum from obese mice, while the shift was observed in the cultures with RLC serum from lean mice. These results showed that the alteration of monocytosis and subsets underlies negating RLC benefits in obese mice and suggest careful considerations of comorbidities at the time of RLC application for stroke therapy.
NairRWagnerANBuckBH.Advances in the management of acute ischemic stroke. Curr Opin Neurol2023;
36: 147–154.
2.
PaulSCandelario-JalilE.Emerging neuroprotective strategies for the treatment of ischemic stroke: an overview of clinical and preclinical studies. Exp Neurol2021;
335: 113518.
3.
BosettiFKoenigJIAyataC, et al.
Translational stroke research: vision and opportunities. Stroke2017;
48: 2632–2637.
4.
GoldsteinLBSamsaGPMatcharDB, et al.
Charlson index comorbidity adjustment for ischemic stroke outcome studies. Stroke2004;
35: 1941–1945.
5.
FischerUArnoldMNedeltchevK, et al.
Impact of comorbidity on ischemic stroke outcome. Acta Neurol Scand2006;
113: 108–113.
6.
BerlowitzDRHoenigHCowperDC, et al.
Impact of comorbidities on stroke rehabilitation outcomes: does the method matter?Arch Phys Med Rehabil2008;
89: 1903–1906.
7.
ChoSYangJ.What do experimental models teach Us about comorbidities in stroke?Stroke2018;
49: 501–507.
8.
KimIDCaveJWChoS.Aflibercept, a VEGF (vascular endothelial growth factor)-trap, reduces vascular permeability and stroke-induced brain swelling in obese mice. Stroke2021;
52: 2637–2648.
9.
KimIDJuHMinklerJ, et al.
Endothelial cell CD36 mediates stroke-induced brain injury via BBB dysfunction and monocyte infiltration in normal and obese conditions. J Cereb Blood Flow Metab2023;
43: 843–855.
10.
OsmondJMMintzJDSteppDW.Preventing increased blood pressure in the obese Zucker rat improves severity of stroke. Am J Physiol Heart Circ Physiol2010;
299: H55–61.
11.
Perez-CorredorPAGutierrez-VargasJACiro-RamirezL, et al.
High fructose diet-induced obesity worsens post-ischemic brain injury in the hippocampus of female rats. Nutr Neurosci2022;
25: 122–136.
12.
NagaiNVan HoefBLijnenHR.Plasminogen activator inhibitor-1 contributes to the deleterious effect of obesity on the outcome of thrombotic ischemic stroke in mice. J Thromb Haemost2007;
5: 1726–1731.
13.
McCollBWRoseNRobsonFH, et al.
Increased brain microvascular MMP-9 and incidence of haemorrhagic transformation in obese mice after experimental stroke. J Cereb Blood Flow Metab2010;
30: 267–272.
14.
WattananitSTorneroDGraubardtN, et al.
Monocyte-derived macrophages contribute to spontaneous long-term functional recovery after stroke in mice. J Neurosci2016;
36: 4182–4195.
15.
JuHParkKWKimID, et al.
Phagocytosis converts infiltrated monocytes to microglia-like phenotype in experimental brain ischemia. J Neuroinflammation2022;
19: 190.
16.
ParkKWJuHKimI-d, et al.
Delayed infiltration of peripheral monocyte contributes to phagocytosis and transneuronal degeneration in chronic stroke. Stroke2022;
53: 2377–2388.
17.
HodaMNSiddiquiSHerbergS, et al.
Remote ischemic perconditioning is effective alone and in combination with intravenous tissue-type plasminogen activator in murine model of embolic stroke. Stroke2012;
43: 2794–2799.
18.
GuoLZhouDWuD, et al.
Short-term remote ischemic conditioning may protect monkeys after ischemic stroke. Ann Clin Transl Neurol2019;
6: 310–323.
19.
YangJBalkayaMBeltranC, et al.
Remote postischemic conditioning promotes stroke recovery by shifting circulating monocytes to CCR2(+) proinflammatory subset. J Neurosci2019;
39: 7778–7789.
20.
WeirPMaguireRO'SullivanSE, et al.
A meta-analysis of remote ischaemic conditioning in experimental stroke. J Cereb Blood Flow Metab2021;
41: 3–13.
21.
OhtsukiTRuetzlerCATasakiK, et al.
Interleukin-1 mediates induction of tolerance to global ischemia in gerbil hippocampal CA1 neurons. J Cereb Blood Flow Metab1996;
16: 1137–1142.
22.
BordetRDeplanqueDMaboudouP, et al.
Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance. J Cereb Blood Flow Metab2000;
20: 1190–1196.
23.
WangPFXiongXYChenJ, et al.
Function and mechanism of toll-like receptors in cerebral ischemic tolerance: from preconditioning to treatment. J Neuroinflammation2015;
12: 80.
24.
McDonoughAWeinsteinJR.Neuroimmune response in ischemic preconditioning. Neurotherapeutics2016;
13: 748–761.
25.
KimEYangJBeltranCD, et al.
Role of spleen-derived monocytes/macrophages in acute ischemic brain injury. J Cereb Blood Flow Metab2014;
34: 1411–1419.
26.
YangJShakilFChoS.Peripheral mechanisms of remote ischemic conditioning. Cond Med2019;
2: 61–68.
27.
BalkayaMKimI-dShakilF, et al.
CD36 deficiency reduces chronic BBB dysfunction and scar formation and improves activity, hedonic and memory deficits in ischemic stroke. J Cereb Blood Flow Metab2021;
41: 486–501.
28.
KimETolhurstATChoS.Deregulation of inflammatory response in the diabetic condition is associated with increased ischemic brain injury. J Neuroinflammation2014;
11: 83.
29.
HerzJHagenSIBergmullerE, et al.
Exacerbation of ischemic brain injury in hypercholesterolemic mice is associated with pronounced changes in peripheral and cerebral immune responses. Neurobiol Dis2014;
62: 456–468.
30.
LiuZJChenCLiXR, et al.
Remote ischemic Preconditioning-Mediated neuroprotection against stroke is associated with significant alterations in peripheral immune responses. CNS Neurosci Ther2016;
22: 43–52.
31.
KimEYangJParkKW, et al.
Inhibition of VEGF signaling reduces Diabetes-Exacerbated brain swelling, but not infarct size, in large cerebral infarction in mice. Transl Stroke Res2018;
9: 540–548.
32.
ZhouYFathaliNLekicT, et al.
Remote limb ischemic postconditioning protects against neonatal hypoxic-ischemic brain injury in rat pups by the opioid receptor/akt pathway. Stroke2011;
42: 439–444.
33.
EnglandTJHedstromAO'SullivanS, et al.
RECAST (remote ischemic conditioning after stroke trial): a pilot randomized placebo controlled phase II trial in acute ischemic stroke. Stroke2017;
48: 1412–1415.
34.
BalamiJSChenRLGrunwaldIQ, et al.
Neurological complications of acute ischaemic stroke. Lancet Neurol2011;
10: 357–371.
35.
KimEFebbraioMBaoY, et al.
CD36 in the periphery and brain synergizes in stroke injury in hyperlipidemia. Ann Neurol2012;
71: 753–764.
36.
HessDCHodaMNKhanMB.Humoral mediators of remote ischemic conditioning: Important role of eNOS/NO/nitrite. Acta Neurochir Suppl2016;
121: 45–48.
37.
RassafTTotzeckMHendgen-CottaUB, et al.
Circulating nitrite contributes to cardioprotection by remote ischemic preconditioning. Circ Res2014;
114: 1601–1610.
38.
StarkopfJBuggeEYtrehusK.Preischemic bradykinin and ischaemic preconditioning in functional recovery of the globally ischaemic rat heart. Cardiovasc Res1997;
33: 63–70.
39.
ChoSParkEMZhouP, et al.
Obligatory role of inducible nitric oxide synthase in ischemic preconditioning. J Cereb Blood Flow Metab2005;
25: 493–501.
40.
ZhuYOhlemillerKKMcMahanBK, et al.
Constitutive nitric oxide synthase activity is required to trigger ischemic tolerance in mouse retina. Exp Eye Res2006;
82: 153–163.
41.
IzuishiKTsungAJeyabalanG, et al.
Cutting edge: high-mobility group box 1 preconditioning protects against liver ischemia-reperfusion injury. J Immunol2006;
176: 7154–7158.
42.
BaranyaiTNagyCTKoncsosG, et al.
Acute hyperglycemia abolishes cardioprotection by remote ischemic perconditioning. Cardiovasc Diabetol2015;
14: 151.
43.
HeinenABehmenburgFAytulunA, et al.
The release of cardioprotective humoral factors after remote ischemic preconditioning in humans is age- and sex-dependent. J Transl Med2018;
16: 112.
44.
BehmenburgFHeinenABruchLV, et al.
Cardioprotection by remote ischemic preconditioning is blocked in the aged rat heart in vivo. J Cardiothorac Vasc Anesth2017;
31: 1223–1226.
45.
RitzelRMLaiYJCrapserJD, et al.
Aging alters the immunological response to ischemic stroke. Acta Neuropathol2018;
136: 89–110.
46.
GhoriAPrinzVNieminen-KehlaM, et al.
Vascular endothelial growth factor augments the tolerance towards cerebral stroke by enhancing neurovascular repair mechanism. Transl Stroke Res2022;
13: 774–791.
47.
ZhanYWangNVasanthakumarA, et al.
CCR2 enhances CD25 expression by FoxP3(+) regulatory T cells and regulates their abundance independently of chemotaxis and CCR2(+) myeloid cells. Cell Mol Immunol2020;
17: 123–132.
48.
BakosEThaissCAKramerMP, et al.
CCR2 regulates the immune response by modulating the interconversion and function of effector and regulatory T cells. J Immunol2017;
198: 4659–4671.
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