Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models

Konstantinos Vanezis,Anissa A Widjaja,Ben Corden,Jinqiao Dong ,G D’agostino ,Benjamin Ng,Stuart A Cook,V Sivakumar ,Sebastian Schäfer ,Nicole Tee ,Nicole S J Ko,Xiu-Yi Kwek,Muhammad Hasan Jamal ,Wei‐Wen Lim ,Chen Xie,Weihua Song ,Beeyong Soh,Mao Wang,Liping Su,Chee Jian Pua

doi:10.1038/s41598-020-74944-7

Abstract

Transforming growth factor beta-1 (TGFβ1) is a major driver of vascular smooth muscle cell (VSMC) phenotypic switching, an important pathobiology in arterial disease.We performed RNA-sequencing of TGFβ1-stimulated human aortic or arterial VSMCs which revealed large and consistent upregulation of Interleukin 11 (IL11). IL11 has an unknown function in VSMCs, which highly express the IL11 receptor alpha, suggestive of an autocrine loop. In vitro, IL11 activated ERK signaling, but inhibited STAT3 activity, and caused VSMC phenotypic switching to a similar extent as TGFβ1 or angiotensin II (ANGII) stimulation. Genetic or therapeutic inhibition of IL11 signaling reduced TGFβ1- or ANGII-induced VSMC phenotypic switching, placing IL11 activity downstream of these factors. Aortas of mice with Myh11-driven IL11 expression were remodeled and had reduced contractile but increased matrix and inflammatory genes expression. In two models of arterial pressure loading, IL11 was upregulated in the aorta and neutralizing IL11 antibodies reduced remodeling along with matrix and pro-inflammatory gene expression. These data show that IL11 plays an important role in VSMC phenotype switching, vascular inflammation and aortic pathobiology.

Highlights

Transforming growth factor beta-1 (TGFβ1) is a major driver of vascular smooth muscle cell (VSMC) phenotypic switching, an important pathobiology in arterial disease.We performed RNA-sequencing of TGFβ1-stimulated human aortic or arterial Vascular smooth muscle cells (VSMCs) which revealed large and consistent upregulation of Interleukin 11 (IL11)
Stimulation of human VSMCs with IL11 (n = 5 biological replicates) increases both (g) tissue inhibitor matrix metalloproteinase 1 (TIMP1) and (h) matrix metalloproteinase 2 (MMP2) secretion. (i) Proliferation (EdU+ve cells) and COL1A1 expression by human VSMCs following IL11, TGFβ1 or angiotensin II (ANGII) stimulation. (j) Collagen secretion as measured by Sirius red collagen detection assay in culture medium following cytokine stimulation (n = 4). (k) VSMC migration measured by scratch wound assay following cytokine stimulation (n = 4). (l) Matrigel invasion indices of VSMCs induced by IL11 (1, 5, and 10 ng/ml), TGFβ1 or ANGII (n = 4)
TGFβ1 has been shown to induce IL11 secretion from aortic and coronary artery V SMCs17,19. This finding, which we confirm, and the fact that VSMCs highly express IL11 receptor alpha (IL11RA), which we demonstrate, suggest the existence of an autocrine loop of IL11 activity in VSMCs