M2 Macrophage-Derived ENPP2/LPA Signalling Attenuates UVB-Induced Fibroblast Photoaging via LPAR1/3
Meiqi Lu1,2,3, Xiaoyang Wang1,2,3, Yujie Hu1,2,3
1The Second Clinical College of Shandong University, Jinan, Shandong, China.
Abstract:
Chronic exposure to ultraviolet B (UVB) radiation induces excessive reactive oxygen species (ROS) production in dermal fibroblasts, leading to cellular senescence and skin photoaging. Ageing skin is characterised by disruption of the immune microenvironment, including impaired macrophage polarisation and reduced M2 macrophage activity. However, the contribution of M2 macrophages to fibroblast photoaging remains incompletely understood. Here, we investigated whether M2 macrophages attenuate UVB-induced fibroblast senescence through ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2)-dependent lysophosphatidic acid (LPA)signalling. UVB-induced L929 fibroblasts were treated with conditioned media derived from polarised RAW264.7 macrophages, with or without ENPP2 silencing. UVB exposure induced marked senescence, oxidative stress, and mitophagy impairment, whereas conditioned medium from M2 macrophages significantly alleviated these effects compared with M1-derived conditioned medium. Notably, ENPP2 depletion in M2 macrophages substantially reduced these protective effects. M2 macrophage-derived conditioned medium contained elevated LPA levels and restored UVB-suppressed LPAR1 and LPAR3 expression in fibroblasts. Pharmacological inhibition of LPAR1/3 attenuated the protective effects of M2 macrophages, while exogenous LPA supplementation restored these effects under ENPP2-deficient conditions. These changes were associated with enhanced PINK1/Parkin-related mitophagy signalling and reduced oxidative stress. Collectively, these findings identify M2 macrophage-derived ENPP2/LPA signalling as a critical paracrine mechanism that mitigates UVB-induced fibroblast photoaging.
Insights
M2 macrophages protect skin cells from sun damage by releasing a molecule that reduces aging. This ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) and lysophosphatidic acid (LPA) pathway is key to preventing photoaging.
Area of Science:
- Dermatology
- Immunology
- Cell Biology
Background:
- Chronic ultraviolet B (UVB) radiation causes skin aging by increasing oxidative stress and cellular senescence in fibroblasts.
- Aging skin exhibits immune dysregulation, including altered macrophage polarization and reduced M2 macrophage function, impacting skin health.
- The specific role of M2 macrophages in mitigating UVB-induced fibroblast photoaging is not fully understood.
Purpose of the Study:
- To investigate if M2 macrophages can reduce UVB-induced fibroblast senescence.
- To determine the involvement of ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2)-dependent lysophosphatidic acid (LPA) signaling in this protective mechanism.
Main Methods:
- UVB-exposed fibroblasts were treated with conditioned media from M1 or M2 polarized macrophages, with or without ENPP2 silencing.
- Lysophosphatidic acid (LPA) levels, macrophage polarization markers, and fibroblast senescence markers were analyzed.
- Expression of LPA receptors (LPAR1, LPAR3) and mitophagy-related proteins (PINK1, Parkin) were assessed.
Main Results:
- M2 macrophage conditioned media significantly alleviated UVB-induced fibroblast senescence, oxidative stress, and mitophagy impairment compared to M1.
- ENPP2 depletion in M2 macrophages diminished these protective effects, highlighting ENPP2's crucial role.
- M2-derived conditioned media increased LPA levels and restored UVB-suppressed LPAR1/LPAR3 expression in fibroblasts, with exogenous LPA rescuing protective effects in ENPP2-deficient conditions.
Conclusions:
- M2 macrophage-derived ENPP2/LPA signaling is a vital paracrine mechanism that combats UVB-induced fibroblast photoaging.
- This pathway enhances mitophagy and reduces oxidative stress, offering a novel therapeutic target for skin aging.
- Understanding this interaction between M2 macrophages and fibroblasts provides insights into immune-mediated skin rejuvenation.