Brain-released alarmins as mediators of immunological comorbidities after stroke
Final Report Abstract
II. SUMMARY Changes to the immune system in the body's periphery are a significant aspect of the systemic effects that occur after a stroke. One prominent phenomenon of post-stroke immunomodulation is an immunosuppressive syndrome in the subacute phase after stroke. However, recent research from our group and others has shown that there is also strong over-activation of the peripheral immune system in the early phase after a stroke, as well as a persistent low-grade inflammatory state in the later stages. These findings suggest that there is a multi-phase systemic immune reaction to a stroke, with brain-released alarmins playing a key role in initiating this dysregulation of peripheral immune homeostasis. The purpose of this project was to investigate the role of alarmins as an upstream mediator of multiple critical comorbidities observed in stroke patients at distinct phases within the immunological cascade after stroke. This project addresses three distinct mechanistic phenomena and their underlying mechanisms as potential drug targets: 1) cytokine-induced sickness-behavior (CISB) due to an alarmin-driven acute cytokine-storm. 2) caspase 1-dependent pyroptotic cell death as the immunophenotypical switch from immune activation to suppression in the subacute phase. 3) the exacerbation of atherosclerosis in the chronic stages after stroke due to alarmin-mediated chronic inflammation. The project was started in February 2016, and should have regularly ended in 01/2021. Due to considerable delays in project progress during the pandemic, the project was prolonged by in total 12 months and ended in January 2022. This cost-neutral project prolongation allowed to reach all project milestones and successfully finish all subprojects within this program. Moreover, it allowed to substantially expand the work program and follow-up exciting novel mechanistic insights beyond the initially proposed experiments. This project led already to publication of several manuscripts in high-impact journals including Immunity and Science Translational Medicine. Another manuscript from subproject 3) on the role of inflammation-driven atherosclerotic lesion progression is currently still in review at Nature Medicine. During the project progress also additional new tools have been established and implemented as routine methods in our laboratory. As such, we developed a novel behavioral test battery to identify CISB-specific deficits in contrast to focal deficits due to strategic brain tissue lesions and validated this test battery in a proof-of-concept trial (Brain, Behav and Immunity, 2021). Additionally, we established in a side-project an automated analysis tool for microglial morphology which has since publication (Front Cell Neurosci, 2018) already been broadly adopted and used in >40 published reports by other groups as we made this tool and source code publicly available. In subproject 2 we have been able to identify a novel form of inflammasome-dependent monocyte- T cell interaction that is the main contributor leading to subacute T cell loss after stroke. These results have been published in 2021 in the journal Immunity, and since then had an impact on our own work—including subproject 3 of this programme—as well as drug development targeting inflammasome-dependent mechanisms by collaborators and in newly established collaborations with pharmaceutical companies (CSL Behring). Moreover, we will follow-up on these preclinical findings by performing a first in human clinical proof-of-concept trial, which is currently in evaluation by the regulatory authorities (BfArM). In subproject 3 we have been able to describe in the first funding period a pro-inflammatory effect of the systemic immune response after stroke which promotes plaque progression in a murine atherosclerosis model (Science Transl Med, 2018). After this early observation in the project progress, we combined this novel information from subprojects 2 and 3 to test a potential role of systemic inflammasome activation after stroke on atherosclerosis progression and atherosclerotic plaque rupture. These additional experiments (which were not part of the original application) have led to unexpected findings with major significance in that they identified DNA-mediated inflammasome activation in atherosclerotic plaques after stroke as a main driver or early recurrent vascular events. Results from this subproject are currently under review at Nature Medicine and expected to be published in 2023.
Publications
- (2017) Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair. Nucleic Acids Res. Oct 13;45(18):10595-10613
Kumar V, […] Isermann B, Liesz A, Deshpande D, Häring HU, Biswas SK, Reynolds PR, Hammes HP, Peperkok R, Angel P, Herzig S, Nawroth PP
(See online at https://doi.org/10.1093/nar/gkx705) - (2018) Automated Morphological Analysis of Microglia After Stroke. Front Cell Neurosci. 12:106
Heindl S, […] Duering M, Liesz A
(See online at https://doi.org/10.3389/fncel.2018.00106) - (2018) Brain-released alarmins and stress response synergize in accelerating atherosclerosis progression after stroke. Science Translational Medicine, Mar 14;10(432)
Roth S, Singh V, Tiedt S, [...] Harris HE, Engelhardt B, Bianchi ME, Vivien D, Bernhagen J, Dichgans M, Liesz A
(See online at https://doi.org/10.1126/scitranslmed.aao1313) - (2019) Panoptic imaging of transparent mice reveals whole-body neuronal projections and skull-meninges connections. Nat Neurosci. 22(2):317-327
Cai R, […] Bechmann I, Liesz A, Menze B, Kerschensteiner M, Nedergaard M, Ertürk A
(See online at https://doi.org/10.1038/s41593-018-0301-3) - (2020) Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability. Circ Res Aug 28;127(6):811-823
Asare Y, Campbell-James TA, […] Malik R, Haffner C, Liesz A, Soehnlein O, Bernhagen J, Dichgans M
(See online at https://doi.org/10.1161/circresaha.120.316743) - (2020) Short-Chain Fatty Acids Improve Poststroke Recovery via Immunological Mechanisms. J Neurosci. Jan 29;40(5):1162-1173
Sadler R, Cramer JV, […] Giera M, Stowe AM, Liesz A
(See online at https://doi.org/10.1523/jneurosci.1359-19.2019) - (2021) Detection of cytokine-induced sickness behavior after ischemic stroke by an optimized behavioral assessment battery. Brain Behav Immun. Jan;91:668-672
Roth S, Yang J, Cramer JV, Malik R, Liesz A
(See online at https://doi.org/10.1016/j.bbi.2020.11.016) - (2021) Post-injury immunosuppression and secondary infections are caused by an AIM2 inflammasomedriven signaling cascade. Immunity Mar 1;S1074-7613(21)00070-4
Roth S, Cao J, Singh V, Tiedt S, […] Zhang S, Groß O, Dichgans M, Hornung V, Liesz A
(See online at https://doi.org/10.1016/j.immuni.2021.02.004) - (2022) Systemic inflammation after stroke: implications for post-stroke comorbidities. EMBO Mol Med. Sep 7;14(9):e16269
Simats A, Liesz A
(See online at https://doi.org/10.15252/emmm.202216269)
