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Silencing of Zc3h13 attenuates LPS-induced inflammatory response in macrophages via m6A-dependent stabilization of
Yaoyun Wang1, Chunai Zhan1, Yuanyuan Zhang1
1Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Pathogen Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
Abstract:
N6-methyladenosine (m6A) represents a reversible and ubiquitous posttranscriptional modification of mRNA. It plays a crucial role in immune cell development and is implicated in a range of pathological conditions. Nevertheless, the precise role of m6A in LPS-induced macrophage inflammatory responses remains elusive. In the present study, we investigated the role of the m6A writer Zc3h13 in LPS-induced liver inflammation. Macrophages, which are vital components of the immune system, play critical roles in liver injury. Our results demonstrate that Zc3h13 is highly expressed in liver macrophages during LPS-induced liver injury and is integral to the regulation of inflammatory factor expression and macrophage polarization. In vivo experiments reveal that knockdown of Zc3h13 alleviates LPS-induced liver inflammation in C57BL/6 murine models. In vitro, Zc3h13 silencing in LPS-stimulated macrophages diminishes m6A methylation, attenuates inflammation, and promotes macrophage polarization from the proinflammatory to anti-inflammatory phenotype. Furthermore, Zc3h13 silencing stabilizes Spic mRNA in an m6A-dependent manner, thereby inhibiting NF-κB pathway activation and alleviating inflammation. Notably, co-silencing of Spic and Zc3h13 reversed the inhibitory effects of Zc3h13 knockdown on inflammatory factor expression and NF-κB pathway activation. In conclusion, our study suggests that Zc3h13 silencing alleviates LPS-induced liver injury through regulation of the NF-κB pathway in macrophages.
Insights
The m6A writer Zc3h13 regulates inflammatory responses in macrophages during LPS-induced liver injury. Silencing Zc3h13 alleviates liver inflammation by stabilizing Spic mRNA and inhibiting the NF-κB pathway.
Area of Science:
- Immunology
- Molecular Biology
- Hepatology
Background:
- N6-methyladenosine (m6A) is a key mRNA modification influencing immune responses.
- The role of m6A in lipopolysaccharide (LPS)-induced macrophage inflammation is not fully understood.
- Macrophages are critical in liver injury and inflammation.
Purpose of the Study:
- To investigate the role of the m6A writer Zc3h13 in LPS-induced liver inflammation.
- To elucidate the mechanisms by which Zc3h13 affects macrophage inflammatory responses.
Main Methods:
- Investigated Zc3h13 expression in LPS-induced liver injury models.
- Utilized in vivo (murine models) and in vitro (macrophage cultures) approaches.
- Examined m6A methylation, inflammatory factor expression, macrophage polarization, and the NF-κB pathway.
Main Results:
- Zc3h13 is upregulated in liver macrophages during LPS-induced injury.
- Zc3h13 knockdown reduced inflammation, diminished m6A levels, and promoted anti-inflammatory macrophage polarization.
- Zc3h13 silencing stabilized Spic mRNA, inhibited NF-κB activation, and alleviated liver inflammation.
- Co-silencing Spic and Zc3h13 reversed these effects.
Conclusions:
- Zc3h13 plays a critical role in regulating LPS-induced liver inflammation via macrophage responses.
- Zc3h13 silencing alleviates liver injury by modulating the Spic mRNA/NF-κB pathway.
- Targeting Zc3h13 presents a potential therapeutic strategy for liver inflammatory diseases.
