The Lipoxin Receptor/FPR2 Agonist BML-111 Protects Mouse Skin Against Ultraviolet B Radiation

Abstract

Excessive exposure to UV, especially UVB, is the most important risk factor for skin cancer and premature skin aging. The identification of the specialized pro-resolving lipid mediators (SPMs) challenged the preexisting paradigm of how inflammation ends. Rather than a passive process, the resolution of inflammation relies on the active production of SPMs, such as Lipoxins (Lx), Maresins, protectins, and Resolvins. LXA4 is an SPM that exerts its action through ALX/FPR2 receptor. Stable ALX/FPR2 agonists are required because SPMs can be quickly metabolized within tissues near the site of formation. BML-111 is a commercially available synthetic ALX/FPR2 receptor agonist with analgesic, antioxidant, and anti-inflammatory properties. Based on that, we aimed to determine the effect of BML-111 in a model of UVB-induced skin inflammation in hairless mice. We demonstrated that BML-111 ameliorates the signs of UVB-induced skin inflammation by reducing neutrophil recruitment and mast cell activation. Reduction of these cells by BML-111 led to lower number of sunburn cells formation, decrease in epidermal thickness, collagen degradation, cytokine production (TNF-α, IL-1β, IL-6, TGF, and IL-10), and oxidative stress (observed by an increase in total antioxidant capacity and Nrf2 signaling pathway), indicating that BML-111 might be a promising drug to treat skin disorders.

The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Exhibits Anti-Inflammatory Activity in LPS-Stimulated Organotypic Hippocampal Cultures

“…Recently, the resolution of inflammation (RoI) was shown to be regulated by specialized pro-resolving mediators (SPMs) [ 6 , 7 ] that are enzymatically derived from essential polyunsaturated fatty acids, including arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid, in a lipoxygenase-dependent manner [ 8 , 9 ]. SPMs exert their biological actions by binding to and activating cognate receptors, of which formyl peptide receptor 2 (FPR2) is of special interest [ 10 , 11 ]. FPR2 (also referred to in the literature as FPRL1 or ALX/FPR2) is a G protein-coupled receptor (GPCR) that binds LXA4 and 15-epi-LXA4 with high affinity.…”

Topical Administration of 15-Deoxy-Δ12,14-Prostaglandin J2 Using a Nonionic Cream: Effect on UVB-Induced Skin Oxidative, Inflammatory, and Histopathological Modifications in Mice

“…Mast cells are tissue-resident cells and one of the first cells to respond to inflammatory stimulation [ 33 ]. UVB irradiation induces the increase of mast cells in the dermis, since their recruitment occurs to amplify the inflammatory response [ 26 ]. In agreement with that, we observed that UVB irradiation successfully increased the number of mast cells in the dermis compared to the naive group and that the uTF was inactive ( Figure 7 ).…”

“…For the determination of epidermal thickness [ 24 ] and for counting the number of sunburn cells [ 25 ], tissue sections were stained with hematoxylin and eosin (H&E) and analyzed using light microscopy at a magnification of 40x and 100x, respectively. Toluidine blue staining was also used to determine mast cell counts (40x magnification) [ 26 ]. Analyses were done with the software Infinity Analyze (Lumenera® Software) [ 20 ].…”

Therapeutic Effects of Specialized Pro-Resolving Lipids Mediators on Cardiac Fibrosis via NRF2 Activation

“…In other words, LXA4 methyl ester activates the ERK/NRF2 signaling pathway in rats, improving cognitive impairment due to chronic decreased cerebral perfusion [ 167 ]. The LXA4 Receptor/FPR2 Agonist BML-111 protected mouse skin from ultraviolet B radiation, and an increase in NRF2 signaling was observed [ 177 ]. BML-111 treatment prevents cardiac cell death and oxidative stress in an autoimmune myocarditis mouse model [ 178 ].…”