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Anti-Inflammatory Role of TRPV4 in Human Macrophages
Yukiko Atsumi1,2, Manami Toriyama1,2,3, Hiroko Kato1,2
1Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Abstract:
The pathology of skin immune diseases such as atopic dermatitis is closely related to the overproduction of cytokines by macrophages. Although the pathological functions of macrophages in skin are known, mechanisms of how they detect the tissue environment remain unknown. TRPV4, a nonselective cation channel with high Ca2+ permeability, is activated at physiological temperatures from 27 to 35°C and involved in the functional control of macrophages. However, the relationship between TRPV4 function in macrophages and skin immune disease is unclear. In this study, we demonstrate that TRPV4 activation inhibits NF-κB signaling, resulting in the suppression of IL-1β production in both human primary monocytes and macrophages derived from human primary monocytes. A TRPV4 activator also inhibited the differentiation of human primary monocytes into GM-CSF M1 macrophages but not M-CSF M2 macrophages. We also observed a significant increase in the number of inducible NO synthase-positive/TRPV4-negative dermal macrophages in atopic dermatitis compared with healthy human skin specimens. Our findings provide insight into the physiological relevance of TRPV4 to the regulation of macrophages during homeostasis maintenance and raise the potential for TRPV4 to be an anti-inflammatory target.
Insights
Transient Receptor Potential Vanilloid 4 (TRPV4) activation suppresses inflammatory IL-1β production by inhibiting NF-κB signaling in macrophages. This suggests TRPV4 is a potential anti-inflammatory target for skin immune diseases.
Area of Science:
- Immunology
- Dermatology
- Cell Biology
Background:
- Skin immune diseases like atopic dermatitis involve macrophage overproduction of cytokines.
- Mechanisms by which skin macrophages sense their environment are not fully understood.
- Transient Receptor Potential Vanilloid 4 (TRPV4) channels regulate macrophage function but their role in skin immunity is unclear.
Purpose of the Study:
- To investigate the role of TRPV4 in regulating macrophage function and its relevance to skin immune diseases.
- To determine if TRPV4 activation affects inflammatory signaling pathways in human monocytes and macrophages.
- To explore the potential of TRPV4 as an anti-inflammatory therapeutic target.
Main Methods:
- Utilized human primary monocytes and derived macrophages.
- Administered TRPV4 activators to assess effects on NF-κB signaling and cytokine production (IL-1β).
- Examined macrophage differentiation into M1 and M2 subtypes.
- Analyzed TRPV4 and inducible NO synthase expression in human skin biopsies from atopic dermatitis patients and healthy controls.
Main Results:
- TRPV4 activation inhibited NF-κB signaling, leading to suppressed IL-1β production in human monocytes and macrophages.
- TRPV4 activators reduced differentiation into M1 macrophages but not M2 macrophages.
- Atopic dermatitis skin showed increased numbers of inducible NO synthase-positive/TRPV4-negative dermal macrophages compared to healthy skin.
Conclusions:
- TRPV4 activation plays a role in suppressing inflammatory responses in macrophages.
- TRPV4 may be involved in maintaining skin homeostasis.
- TRPV4 represents a potential therapeutic target for treating inflammatory skin conditions like atopic dermatitis.
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