Paracrine Interleukin 6 Induces Cerebral Remodeling at Early Stages After Unilateral Common Carotid Artery Occlusion in Mice

Melanie T C Kuffner; Stefan P Koch; Marieluise Kirchner; Susanne Mueller; Janet Lips; Jeehye An; Philipp Mertins; Ulrich Dirnagl; Matthias Endres; Philipp Boehm-Sturm; Christoph Harms; Christian J Hoffmann

doi:10.3389/fcvm.2021.805095

Paracrine Interleukin 6 Induces Cerebral Remodeling at Early Stages After Unilateral Common Carotid Artery Occlusion in Mice

Front Cardiovasc Med. 2022 Jan 27:8:805095. doi: 10.3389/fcvm.2021.805095. eCollection 2021.

Authors

Melanie T C Kuffner¹, Stefan P Koch^{1

2

3}, Marieluise Kirchner⁴, Susanne Mueller^{1

2

3}, Janet Lips¹, Jeehye An^{1

2

3}, Philipp Mertins⁴, Ulrich Dirnagl^{1

2

5

6

7

8

9}, Matthias Endres^{1

2

5

6

7

8}, Philipp Boehm-Sturm^{1

2

3}, Christoph Harms^{1

2

5

8}, Christian J Hoffmann^{1

2}

Affiliations

¹ Klinik und Hochschulambulanz für Neurologie mit Experimenteller Neurologie, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
² Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
³ NeuroCure Cluster of Excellence and Charité Core Facility 7T Experimental MRIs, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁴ Core Unit Proteomics, Berlin Institute of Health at Charité- Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
⁵ German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany.
⁶ NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁷ German Center for Neurodegenerative Diseases (DZNE), Partner Site Berlin, Berlin, Germany.
⁸ Einstein Center for Neuroscience, Berlin, Germany.
⁹ QUEST Quality, Ethics, Open Science, Translation, Center for Transforming Biomedical Research, Berlin Institute of Health, Berlin, Germany.

Abstract

Aims: Carotid artery disease is frequent and can result in chronic modest hypoperfusion of the brain. If no transient ischemic attack or stroke occur, it is classified asymptomatic. In the long-term, though, it can lead to cognitive impairment. Fostering cerebral remodeling after carotid artery occlusion might be a new concept of treatment. Paracrine Interleukin 6 (IL-6) can induce such remodeling processes at early stages. However, it has neurodegenerative long-term effects. With this exploratory study, we investigated the effect of paracrine IL-6 on cerebral remodeling in early stages after asymptomatic carotid artery occlusion to identify new treatment targets.

Methods and results: To mimic a human asymptomatic carotid artery disease, we used a mouse model of unilateral common carotid artery (CCA) occlusion. We developed a mouse model for inducible paracrine cerebral IL-6 expression (Cx30-Cre-ERT2;FLEX-IL6) and induced IL-6 2 days after CCA occlusion. We studied the effects of paracrine IL-6 after CCA occlusion on neuronal connectivity using diffusion tensor imaging and on local proteome regulations of the hypo-perfused striatum and contralateral motor cortex using mass spectrometry of laser capture micro-dissected tissues. Paracrine IL-6 induced cerebral remodeling leading to increased inter-hemispheric connectivity and changes in motor system connectivity. We identified changes in local protein abundance which might have adverse effects on functional outcome such as upregulation of Synuclein gamma (Sncg) or downregulation of Proline Dehydrogenase 1 (Prodh). However, we also identified changes in local protein abundance having potentially beneficial effects such as upregulation of Caprin1 or downregulation of GABA transporter 1 (Gat1).

Conclusions: Paracrine cerebral IL-6 at early stages induces changes in motor system connectivity and the proteome after asymptomatic CCA occlusion. Our results may help to distinguish unfavorable from beneficial IL-6 dependent protein regulations. Focusing on these targets might generate new treatments to improve long-term outcome in patients with carotid artery disease.

Keywords: basic science research; carotid artery occlusion; inflammation; proteomics; vascular disease.