TY - JOUR
T1 - Remote ischemic post-conditioning promotes hematoma resolution via AMPK-dependent immune regulation
AU - Vaibhav, Kumar
AU - Braun, Molly
AU - Khan, Mohammad Badruzzaman
AU - Fatima, Sumbul
AU - Saad, Nancy
AU - Shankar, Adarsh
AU - Khan, Zenab T.
AU - Harris, Ruth B.S.
AU - Yang, Qiuhua
AU - Huo, Yuqing
AU - Arbab, Ali S.
AU - Giri, Shailendra
AU - Alleyne, Cargill Herley
AU - Vender, John R.
AU - Hess, David C.
AU - Baban, Babak
AU - Hoda, MD Nasrul
AU - Dhandapani, Krishnan M.
N1 - Funding Information:
Financial support for this project was provided by grants from the National Institutes of Health (grants NS065172, NS095154, NS075774, NS084228, and NS097825) and American Heart Association (GRNT33700286) to K.M. Dhandapani and from the National Institutes of Health (grants NS099455 and NS090609) to D.C. Hess. The authors declare no competing financial interests.
Publisher Copyright:
© 2018 Vaibhav et al.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - Spontaneous intracerebral hemorrhage (ICH) produces the highest acute mortality and worst outcomes of all stroke subtypes. Hematoma volume is an independent determinant of ICH patient outcomes, making clot resolution a primary goal of clinical management. Herein, remote-limb ischemic post-conditioning (RIC), the repetitive inflation-deflation of a blood pressure cuff on a limb, accelerated hematoma resolution and improved neurological outcomes after ICH in mice. Parabiosis studies revealed RIC accelerated clot resolution via a humoral-mediated mechanism. Whereas RIC increased anti-inflammatory macrophage activation, myeloid cell depletion eliminated the beneficial effects of RIC after ICH. Myeloid-specific inactivation of the metabolic regulator, AMPKα1, attenuated RIC-induced anti-inflammatory macrophage polarization and delayed hematoma resolution, providing a molecular link between RIC and immune activation. Finally, chimera studies implicated myeloid CD36 expression in RIC-mediated neurological recovery after ICH. Thus, RIC, a clinically well-tolerated therapy, noninvasively modulates innate immune responses to improve ICH outcomes. Moreover, immunometabolic changes may provide pharmacodynamic blood biomarkers to clinically monitor the therapeutic efficacy of RIC.
AB - Spontaneous intracerebral hemorrhage (ICH) produces the highest acute mortality and worst outcomes of all stroke subtypes. Hematoma volume is an independent determinant of ICH patient outcomes, making clot resolution a primary goal of clinical management. Herein, remote-limb ischemic post-conditioning (RIC), the repetitive inflation-deflation of a blood pressure cuff on a limb, accelerated hematoma resolution and improved neurological outcomes after ICH in mice. Parabiosis studies revealed RIC accelerated clot resolution via a humoral-mediated mechanism. Whereas RIC increased anti-inflammatory macrophage activation, myeloid cell depletion eliminated the beneficial effects of RIC after ICH. Myeloid-specific inactivation of the metabolic regulator, AMPKα1, attenuated RIC-induced anti-inflammatory macrophage polarization and delayed hematoma resolution, providing a molecular link between RIC and immune activation. Finally, chimera studies implicated myeloid CD36 expression in RIC-mediated neurological recovery after ICH. Thus, RIC, a clinically well-tolerated therapy, noninvasively modulates innate immune responses to improve ICH outcomes. Moreover, immunometabolic changes may provide pharmacodynamic blood biomarkers to clinically monitor the therapeutic efficacy of RIC.
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U2 - 10.1084/JEM.20171905
DO - 10.1084/JEM.20171905
M3 - Article
C2 - 30190288
AN - SCOPUS:85054058247
SN - 0022-1007
VL - 215
SP - 2636
EP - 2654
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 10
ER -