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bioRxiv · 10.1101/2023.05.23.542025

Interleukin-16/STAT6 recruits CBP/p300 to upregulate TIMP-3 and promote atherosclerotic plaque stability

He, H.·Ding, M.·Zhu, Y.·Jiang, T.·Dong, D.·Xu, X.·Ou, H.
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Abstract

BackgroundAtherosclerotic plaque rupture increases the risk of ischemic heart disease and stroke and commonly causes sudden death. High levels of circulating or intraplaque interleukin 16 (IL-16) are clinically associated with a reduced incidence of cardiovascular events. Here, we investigated the effects of IL-16 on plaque phenotypic modification and identified the molecules involved in smooth muscle cells (SMCs). MethodsWe deleted IL-16 in ApoE-/- mice to generate IL16-/-ApoE-/- mice, and the double mutant was used for plaque phenotype analysis after a 24-week high-fat diet. RNA sequencing was performed to identify the changes in cellular processes and molecule expression in response to IL-16 defects. Affinity purification-mass spectrometry was used to identify the STAT6 binding protein. Bone marrow transplantation was used to investigate the effects of hematopoietic IL-16 deficiency or reconstitution on plaque stability. ResultsIL-16 deficiency reduced collagen deposition and increased the necrotic core area in the plaques of the brachiocephalic artery and aortic root lesions. Intraplaque TIMP-3 levels were found to be decreased in association with an increase in the proteolytic activity of MMPsinIL16-/-ApoE-/- mice. Next, we demonstrated that IL-16 activates the CD4/JAK2/STAT6 pathway and that STAT6 directly binds the TIMP-3 promoter in SMCs. Furthermore, IL-16 treatment increased the interaction of cAMP-response element binding protein (CBP)/p300 with STAT6, which promoted STAT6 acetylation and increased histone H3 acetylation in the TIMP-3 promoter. Inhibition of CBP/p300 resulted in decreased acetylation of STAT6 and TIMP-3 promoter histone H3 and TIMP-3 expression, suggesting a requirement for CBP/p300 as a coactivator. Finally, we found that hematopoietic-derived IL-16 from ApoE-/- mice or overexpression of TIMP-3 successfully attenuated plaque instability in IL16-/-ApoE-/- mice. ConclusionsIL-6 upregulates TIMP-3 expression and remodels the intraplaque extracellular matrix toward a stable phenotype, suggesting IL-16 as a potential target for intervening in atherosclerosis at later stages.

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He, H., Ding, M., Zhu, Y., Jiang, T., Dong, D., Xu, X., Ou, H.. 2023-05-24. Interleukin-16/STAT6 recruits CBP/p300 to upregulate TIMP-3 and promote atherosclerotic plaque stability. https://doi.org/10.1101/2023.05.23.542025

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