Regulatory role of IKKɑ in myocardial ischemia/reperfusion injury by the determination of M1 versus M2 polarization of macrophages

• Published in: Journal of molecular and cellular cardiology 2018-10, Vol.123, p.1-12
• Main Authors: Cao, Yide, Xu, Yueyue, Auchoybur, Merveesh Luveanand, Chen, Wen, He, Shuai, Qin, Wei, Su, Cunhua, Huang, Fuhua, Qiu, Zhibing, Li, Liangpeng, Chen, Xin
• Format: Article
• Language: English
• Subjects: IKKɑ; Macrophages polarization; MEK1/2/ERK1/2; Myocardial ischemia and reperfusion injury; NF-κB
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2018.08.021

The IκB kinase (IKK) complex plays a well-documented role in cancer and immune system. This function has been widely attributed to its role as the master regulator of the NF-κB family. Particularly, IKKɑ, a member of IKK complex, is reported to have various regulating effects in inflammatory and malignant diseases. However, its role as well as its mechanism of function in macrophages following myocardial ischemia and reperfusion (I/R) injury remains unexplored. In vivo, sham or I/R operations were performed on macrophage-specific IKKɑ knockout (mIKKɑ−/−) mice and their IKKɑflox/flox littermates. We ligated the left anterior descending (LAD) coronary artery of I/R groups simulating ischemia for 30 min, followed by a reperfusion period of 3 days and 7 days, respectively. The hearts of mIKKɑ−/− mice exhibited significantly increased inflammation and macrophage aggregation as compared to their IKKɑflox/flox littermates. Moreover, in the mIKKɑ−/− group subjected to I/R macrophages had a tendency to polarize to M1 phenotype. In vitro, we stimulated RAW264.7 cells with Lipopolysaccharides (LPS) after infection by the lentivirus, either knocking-down or overexpressing IKKɑ. We discovered that a deficiency of IKKɑ in RAW264.7 caused increased expression of pro-inflammatory markers compared to normal RAW264.7 after LPS stimulation. Inversely, pro-inflammatory factors were inhibited with IKKɑ overexpression. Mechanistically, IKKɑ directly combined with RelB to regulate macrophage polarization. Furthermore, IKKɑ regulated MEK1/2-ERK1/2 and downstream p65 signaling cascades after LPS stimulation. Overall, our data reveals that IKKɑ is a novel mediator protecting against the development of myocardial I/R injury via negative regulation of macrophage polarization to M1 phenotype. Thus, IKKɑ may serve as a valuable therapeutic target for the treatment of myocardial I/R injury. •Inflammatory response is an important phase after myocardial ischemia and reperfusion injury.•Macrophage plays a key role at the inflammatory reaction by polarizing to M1 or M2 phenotype.•IKKα is an essential negative regulator inhibiting macrophage polarizing to M1 phenotype.•IKKα is the direct kinase activating RelB in NF-κB alternative pathway.