M2 Macrophage-Derived ENPP2/LPA Signalling Attenuates UVB-Induced Fibroblast Photoaging via LPAR1/3

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.