Abstract
NLR Family CARD Domain Containing 5 (NLRC5), an important immune regulator in innate immunity, is involved in regulating inflammation and antigen presentation. However, the role of NLRC5 in vascular remodeling remains unknown. Here we report the role of NLRC5 on vascular remodeling and provide a better understanding of its underlying mechanism. Nlrc5 knockout (Nlrc5−/−) mice exhibit more severe intimal hyperplasia compared with wild-type mice after carotid ligation. Ex vivo data shows that NLRC5 deficiency leads to increased proliferation and migration of human aortic smooth muscle cells (HASMCs). NLRC5 binds to PPARγ and inhibits HASMC dedifferentiation. NACHT domain of NLRC5 is essential for the interaction with PPARγ and stimulation of PPARγ activity. Pioglitazone significantly rescues excessive intimal hyperplasia in Nlrc5−/− mice and attenuates the increased proliferation and dedifferentiation in NLRC5-deficient HASMCs. Our study demonstrates that NLRC5 regulates vascular remodeling by directly inhibiting SMC dysfunction via its interaction with PPARγ.
Highlights
Nod-like receptors (NLRs) Family CARD Domain Containing 5 (NLRC5), an important immune regulator in innate immunity, is involved in regulating inflammation and antigen presentation
Compared with normal coronary arteries, NLR Family CARD Domain Containing 5 (NLRC5) expression was more abundant in vascular smooth muscle cells (VSMCs) in both Kawasaki disease (Supplementary Fig. 1) and coronary plaques; its expression was ubiquitous, rather than localized in the proliferative medial layer (Fig. 1a–c and Supplementary Fig. 2)
Since we observed that NLRC5 located in the nuclei of VSMCs in mouse carotid tissues in response to injury, we examined NLRC5 expression in the cytoplasmic and nuclear fractions of PDGF-BBstimulated human aortic smooth muscle cells (HASMCs)
Summary
NLR Family CARD Domain Containing 5 (NLRC5), an important immune regulator in innate immunity, is involved in regulating inflammation and antigen presentation. Pioglitazone significantly rescues excessive intimal hyperplasia in Nlrc5−/− mice and attenuates the increased proliferation and dedifferentiation in NLRC5-deficient HASMCs. Our study demonstrates that NLRC5 regulates vascular remodeling by directly inhibiting SMC dysfunction via its interaction with PPARγ. Medical therapies for inhibiting intima hyperplasia are limited This is largely because mechanisms through which these immune modulators regulate vascular remodeling are poorly understood. NLRC5 shuttles between the cytoplasm and the nucleus in a cytokine response modifier A-dependent manner and acts as a key regulator of major histocompatibility complex (MHC) class Idependent immune responses by cooperating with regulatory factor X5 (RFX5)[17,18,19] It negatively regulates the NF-κB signaling, type I interferon activities, and the JAK2/ STAT3-signaling pathway[20,21]. We show a mechanistic link between NLRC5 and PPARγ
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