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

• DOI: 10.1038/s41467-022-34971-6
• Publication Date: 2022-11-30T13:08:23Z
• Authors: 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; Enrico Petretto
• Keywords: Cardiac Fibrosis; Monocyte

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 etiopathology but giving their heterogeneity and antagonizing roles macrophage subtypes targeting these cells has been challenging. Here we focus on WWP2, an E3 ubiquitin ligase that acts as a positive genetic regulator human murine show myeloid specific deletion WWP2 reduces fibrosis hypertension-induced NICM. By using single cell RNA sequencing analysis immune same model, establish functional macrophages define early pro-fibrogenic phase NICM is driven by Ccl5- expressing Ly6c high monocytes. Among subtypes, primarily affects monocytes via modulating Ccl5, consequentially infiltration activation, contributes reduced myofibroblast trans -differentiation. interacts with transcription factor IRF7, promoting its non-degradative mono-ubiquitination, nuclear translocation transcriptional activity, leading upregulation Ccl5 at level. We identify subtype non-ischemic cardiomyopathy, demonstrate key IRF7-mediated Ccl5/Ly6c monocyte axis heart fibrosis.