The E3 ubiquitin ligase WWP2 regulates pro-fibrogenic monocyte infiltration and activity in heart fibrosis

Huimei Chen (), Gabriel Chew, Nithya Devapragash, Jui Zhi Loh, Kevin Y. Huang, Jing Guo, Shiyang Liu, Elisabeth Li Sa Tan, Shuang Chen, Nicole Gui Zhen Tee, Masum M. Mia, Manvendra K. Singh, Aihua Zhang, Jacques Behmoaras () and Enrico Petretto ()
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Huimei Chen: Duke-NUS Medical School
Gabriel Chew: Duke-NUS Medical School
Nithya Devapragash: Duke-NUS Medical School
Jui Zhi Loh: Duke-NUS Medical School
Kevin Y. Huang: Duke-NUS Medical School
Jing Guo: Duke-NUS Medical School
Shiyang Liu: Duke-NUS Medical School
Elisabeth Li Sa Tan: Duke-NUS Medical School
Shuang Chen: China Pharmaceutical University
Nicole Gui Zhen Tee: National Heart Centre Singapore
Masum M. Mia: Duke-NUS Medical School
Manvendra K. Singh: Duke-NUS Medical School
Aihua Zhang: Children’s Hospital of Nanjing Medical University
Jacques Behmoaras: Duke-NUS Medical School
Enrico Petretto: Duke-NUS Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: Abstract Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fibrosis, which corresponds to the failure of cardiac tissue remodeling. Recent evidence implicates monocytes/macrophages in the etiopathology of cardiac fibrosis, but giving their heterogeneity and the antagonizing roles of macrophage subtypes in fibrosis, targeting these cells has been challenging. Here we focus on WWP2, an E3 ubiquitin ligase that acts as a positive genetic regulator of human and murine cardiac fibrosis, and show that myeloid specific deletion of WWP2 reduces cardiac fibrosis in hypertension-induced NICM. By using single cell RNA sequencing analysis of immune cells in the same model, we establish the functional heterogeneity of macrophages and define an early pro-fibrogenic phase of NICM that is driven by Ccl5-expressing Ly6chigh monocytes. Among cardiac macrophage subtypes, WWP2 dysfunction primarily affects Ly6chigh monocytes via modulating Ccl5, and consequentially macrophage infiltration and activation, which contributes to reduced myofibroblast trans-differentiation. WWP2 interacts with transcription factor IRF7, promoting its non-degradative mono-ubiquitination, nuclear translocation and transcriptional activity, leading to upregulation of Ccl5 at transcriptional level. We identify a pro-fibrogenic macrophage subtype in non-ischemic cardiomyopathy, and demonstrate that WWP2 is a key regulator of IRF7-mediated Ccl5/Ly6chigh monocyte axis in heart fibrosis.

Date: 2022
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DOI: 10.1038/s41467-022-34971-6

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