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Meteorin-like protein/METRNL/Interleukin-41 ameliorates atopic dermatitis-like inflammation
Danqi Huang1, Xiuting Liu2, Xun Gao1,3
1Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, China.
Background:
Meteorin-like protein (METRNL)/Interleukin-41 (IL-41) is a novel immune-secreted cytokine/myokine involved in several inflammatory diseases. However, how METRNL exerts its regulatory properties on skin inflammation remains elusive. This study aims to elucidate the functionality and regulatory mechanism of METRNL in atopic dermatitis (AD).
Methods:
METRNL levels were determined in skin and serum samples from patients with AD and subsequently verified in the vitamin D3 analogue MC903-induced AD-like mice model. The cellular target of METRNL activity was identified by multiplex immunostaining, single-cell RNA-seq and RNA-seq.
Results:
METRNL was significantly upregulated in lesions and serum of patients with dermatitis compared to healthy controls (p <.05). Following repeated MC903 exposure, AD model mice displayed elevated levels of METRNL in both ears and serum. Administration of recombinant murine METRNL protein (rmMETRNL) ameliorated allergic skin inflammation and hallmarks of AD in mice, whereas blocking of METRNL signaling led to the opposite. METRNL enhanced β-Catenin activation, limited the expression of Th2-related molecules that attract the accumulation of Arginase-1 (Arg1)hi macrophages, dendritic cells, and activated mast cells.
Conclusions:
METRNL can bind to KIT receptor and subsequently alleviate the allergic inflammation of AD by inhibiting the expansion of immune cells, and downregulating inflammatory gene expression by regulating the level of active WNT pathway molecule β-Catenin.
Insights
Meteorin-like protein (METRNL) alleviates atopic dermatitis (AD) by inhibiting immune cell expansion and inflammation. This novel cytokine targets the KIT receptor, enhancing the WNT pathway for therapeutic potential in skin diseases.
Area of Science:
- Immunology
- Dermatology
- Molecular Biology
Background:
- Meteorin-like protein (METRNL), also known as Interleukin-41 (IL-41), is an emerging cytokine implicated in inflammatory conditions.
- The precise role of METRNL in regulating skin inflammation, particularly in atopic dermatitis (AD), is not well understood.
Purpose of the Study:
- To investigate the functional role and underlying regulatory mechanisms of METRNL in the context of atopic dermatitis.
- To determine if METRNL can be a therapeutic target for AD.
Main Methods:
- Quantified METRNL levels in skin and serum from AD patients and an MC903-induced mouse model.
- Utilized multiplex immunostaining, single-cell RNA-seq, and RNA-seq to identify METRNL's cellular targets and pathways.
Main Results:
- METRNL levels were significantly elevated in AD patients and the mouse model.
- Recombinant METRNL (rmMETRNL) administration reduced AD-like skin inflammation in mice.
- METRNL was found to enhance β-Catenin activation and limit Th2-related molecules and immune cell accumulation.
Conclusions:
- METRNL binds to the KIT receptor to mitigate allergic skin inflammation in AD.
- METRNL inhibits immune cell expansion and downregulates inflammatory gene expression via β-Catenin regulation.
