CD137 Ligand-CD137 Interaction is Required For Inflammasome-Associated Brain Injury Following Ischemic Stroke
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CD137 Ligand‑CD137 Interaction is Required For Inflammasome‑Associated Brain Injury Following Ischemic Stroke David Y. Fann1,2 · Emily Pauline Nickles1,3 · Luting Poh1,4 · Vismitha Rajeev1,4 · Sharmelee Selvaraji1,4,5 · Herbert Schwarz1,3 · Thiruma V. Arumugam1,6,7 Received: 28 August 2020 / Accepted: 8 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The CD137L-CD137 axis is a potent co-stimulatory immune checkpoint regulator that forms a bidirectional signaling pathway between the CD137 ligand (CD137L) and CD137 receptor to regulate immunological activities. This study investigated the potential involvement of the CD137L-CD137 axis on inflammasome-associated brain injury and neurological deficits in a mouse model of focal ischemic stroke. Cerebral ischemia was induced in male C57BL/6J wild-type (WT), CD137L-deficient (CD137L KO) and CD137-deficient (CD137 KO) mice by middle cerebral artery occlusion (MCAO; 60 min), followed by reperfusion (6 h and 24 h). Brain infarct volume and neurological deficit scores were significantly lower in both CD137L KO and CD137 KO mice compared to WT controls. Moreover, CD137L-deficient brains had significantly lower levels of the pyroptotic protein, NT-Gasdermin D, while CD137-deficient brains had significantly lower levels of the pro-apoptotic proteins, cleaved caspase-3, pyroptotic protein, NT-Gasdermin D, and of the secondary pyroptotic protein NT-Gasdermin E, following ischemic stroke. This protection by CD137L and CD137 deletion was associated with a significant decrease in inflammasome signaling. In conclusion, our data provide evidence for the first time that the CD137L-CD137 axis contributes to brain injury and neurological deficits by activating the inflammasome signaling pathway following ischemic stroke. Keywords Inflammasome · Stroke · CD137L · CD137 · Brain injury
Introduction The activation of the co-stimulatory immune checkpoint regulator, CD137, leads to stimulation of multiple intracellular signaling mechanisms that are known to play a role in Emily Pauline Nickles and Luting Poh are contributed equally. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12017-020-08623-1) contains supplementary material, which is available to authorized users. * Thiruma V. Arumugam [email protected] 1
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2
3
Immunology Programme, National University of Singapore, Singapore, Singapore
immunity and a number of disease conditions (Luu et al. 2020; Wong and Schwarz 2020). The interaction between CD137L on antigen presenting cells (APC) and CD137 on activated T and natural killer cells contributes to their activation and survival and potently enhances anti-tumor immune responses (Etxeberria et al. 2020). CD137 ligand (CD137L)
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