Abstract 4145097: IL-6 based designer cytokine IC7 ameliorates cardiac function by shaping immune response in the infarcted mouse heart

Introduction: In the setting of myocardial infarction (MI), the IL-6 cytokine family members, including IL-6 and CNTF, entail the potential to protect the myocardium against ischemia / reperfusion injury. Activation of gp130, the common β receptor for the IL-6 family cytokines, has been implicated to play a pivotal role in cardiac regeneration in neonatal mice and its downstream STAT3 signaling is known to protect the heart via a pre-conditioning manner. Thus, we engineered the chimeric cytokine IC7, a hybrid between IL-6 and CNTF, in which one gp130 binding site of IL-6 was substituted by a CNTF binding site that is capable of binding to LIFR. In the present study, we aim to examine the impact of the novel chimeric cytokine IC7 on cardiac function after MI. Methods: Mice underwent LAD ligation surgery and received IC7 i.p. either before or after and 24 hours after surgery. Cardiac function and structural benefits were evaluated by echocardiography and histological analysis (TTC and trichrome staining). Cardiac bulk RNA-Seq was employed to delve into the mechanistical basis by which IC7 regulated cellular process at transcriptional level. Results: IC7 injection prior to ischemic episode ameliorated ejection fraction (41.44% vs. 26.78%; p<0.01) and prevented pathological cardiac remodeling in the infarcted heart (end-diastolic volume 84.48 µl vs. 107.15 µl; p<0.05), starting from 1 week after surgery, while injection after ischemia reverted the benefits. This is in line with the histological findings from trichrome staining, confirming the results with decreased collagen volume fraction (7.89% vs. 14.01% ; p<0.05) and higher average wall thickness (0.81 mm vs. 0.57 mm ; p<0.05). Interestingly, TTC staining 24 hours after ischemia already revealed significant cardiomyocyte survival within the infarct zone after IC7 treatment (26.92% vs. 13.98% ; p<0.05). On a transcriptome level, RNA-Seq data unveils 24 up- and 14 downregulated genes in the IC7 treated heart, while IC7 in healthy hearts significantly upregulated 62 and downregulated 35 changed genes, primarily enriched with GO terms associated with immune response. Conclusions: Taken together, our results show, for the first time, how a synthetic cytokine (IC7) shapes the cardiac immune response to ischemic injury, leading to remarkably enhanced cardiomyocyte survival and alleviated cardiac remodeling. This finding points to a new promising category of therapeutics for ischemic heart disease.