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YAP Aggravates Inflammatory Bowel Disease by Regulating M1/M2 Macrophage Polarization and Gut Microbial Homeostasis
Xin Zhou1, Weiyun Li1, Shuang Wang1
1State Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai 200031, China.
Abstract:
Inflammation, epithelial cell regeneration, macrophage polarization, and gut microbial homeostasis are critical for the pathological processes associated with inflammatory bowel disease (IBD). YAP (Yes-associated protein) is a key component of the Hippo pathway and was recently suggested to promote epithelial cell regeneration for IBD recovery. However, it is unclear how YAP regulates macrophage polarization, inflammation, and gut microbial homeostasis. Although YAP has been shown to promote epithelial regeneration and alleviate IBD, here we show that YAP in macrophages aggravates IBD, accompanied by the production of antimicrobial peptides and changes in gut microbiota. YAP impairs interleukin-4 (IL-4)/IL-13-induced M2 macrophage polarization while promoting lipopolysaccharide (LPS)/interferon γ (IFN-γ)-triggered M1 macrophage activation for IL-6 production. In addition, YAP expression is differently regulated during the induction of M2 versus M1 macrophages. This study suggests that fully understanding the multiple functions of YAP in different cell types is crucial for IBD therapy.
Insights
Yes-associated protein (YAP) in macrophages worsens inflammatory bowel disease (IBD) by promoting M1 macrophage activation and altering gut microbiota, despite its known role in epithelial repair.
Area of Science:
- Immunology
- Gastroenterology
- Cell Biology
Background:
- Inflammatory bowel disease (IBD) involves complex immune dysregulation, including inflammation, macrophage polarization, and gut microbial imbalance.
- The Hippo pathway component Yes-associated protein (YAP) is implicated in epithelial regeneration, potentially aiding IBD recovery.
- The specific role of YAP in macrophage function and its impact on IBD pathogenesis remain incompletely understood.
Purpose of the Study:
- To investigate the role of YAP in macrophage polarization, inflammation, and gut microbial homeostasis in the context of IBD.
- To elucidate how YAP influences different macrophage activation states (M1 vs. M2) and their associated cytokine production.
- To determine the net effect of YAP in macrophages on IBD progression.
Main Methods:
- Investigated YAP's role in macrophage polarization using in vitro models of M1 and M2 activation.
- Analyzed YAP's impact on cytokine production, including IL-6, IL-4, and IL-13.
- Assessed YAP's effects on antimicrobial peptide production and gut microbiota composition in IBD models.
- Examined YAP expression patterns during M1 and M2 macrophage differentiation.
Main Results:
- YAP expression in macrophages exacerbates IBD, contrary to its beneficial role in epithelial cells.
- YAP impairs M2 macrophage polarization induced by IL-4/IL-13.
- YAP promotes M1 macrophage activation triggered by LPS/IFN-γ, leading to increased IL-6 production.
- YAP influences the production of antimicrobial peptides and alters gut microbial composition in IBD.
Conclusions:
- YAP plays a detrimental role in IBD when expressed in macrophages, promoting pro-inflammatory M1 phenotypes.
- Understanding YAP's context-dependent functions in different cell types is critical for developing effective IBD therapies.
- Targeting YAP in specific immune cells may offer a novel therapeutic strategy for IBD.
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