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. 2024 Mar 4;14(1):5256.
doi: 10.1038/s41598-024-53990-5.

A chronic pro-inflammatory environment contributes to the physiopathology of actinic lentigines

Christine Duval  1 , Emilie Bourreau  2 , Emilie Warrick  2 , Philippe Bastien  2 , Stéphanie Nouveau  2 , Françoise Bernerd  2
Affiliations

A chronic pro-inflammatory environment contributes to the physiopathology of actinic lentigines

Christine Duval et al. Sci Rep. .

Abstract

Actinic lentigines (AL) or age spots, are skin hyperpigmented lesions associated with age and chronic sun exposure. To better understand the physiopathology of AL, we have characterized the inflammation response in AL of European and Japanese volunteers. Gene expression profile showed that in both populations, 10% of the modulated genes in AL versus adjacent non lesional skin (NL), i.e. 31 genes, are associated with inflammation/immune process. A pro-inflammatory environment in AL is strongly suggested by the activation of the arachidonic acid cascade and the plasmin pathway leading to prostaglandin production, along with the decrease of anti-inflammatory cytokines and the identification of inflammatory upstream regulators. Furthermore, in line with the over-expression of genes associated with the recruitment and activation of immune cells, immunostaining on skin sections revealed a significant infiltration of CD68+ macrophages and CD4+ T-cells in the dermis of AL. Strikingly, investigation of infiltrated macrophage subsets evidenced a significant increase of pro-inflammatory CD80+/CD68+ M1 macrophages in AL compared to NL. In conclusion, a chronic inflammation, sustained by pro-inflammatory mediators and infiltration of immune cells, particularly pro-inflammatory M1 macrophages, takes place in AL. This pro-inflammatory loop should be thus broken to normalize skin and improve the efficacy of age spot treatment.

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Conflict of interest statement

All authors are employees of L’Oréal.

Figures

Figure 1
Figure 1
Immunostaining of inflammatory/immune cells in sections of AL and NL from European volunteers. (a) Representative illustration of HLA-DR staining in AL and NL sections of one volunteer, and plots of quantitative analysis of HLA-DR staining surface on skin sections of the epidermis and the dermis for each volunteer (n = 14). (b) Plots of elastase, CD11c, CD117 or CD8 positive cells quantified by image analysis in the dermis of AL and NL for each volunteer (n = 14). (c) Representative illustration of CD68 and CD4 staining in AL and NL sections of one volunteer and plots of CD68 and CD4 positive cells quantified in the dermis for each volunteer (n = 14). Inserts show high magnification of one CD68+ or CD4+ cell from black rectangles. Scale bars: main image 50 µm, insert 10 µm. Statistic comparisons between NL and AL groups were carried out using paired Wilcoxon signed ranks test: *p < 0.05; **p < 0.01; ns: non-significant difference. HLA-DR staining was significantly increased in the dermis of AL versus NL. No significant modulation of the number of elastase, CD11C, CD117 and CD8 positive cells was found. A significant increase of the number of CD68 and CD4 positive cells was revealed in the dermis of AL versus NL.
Figure 2
Figure 2
Identification and comparison of macrophages subsets in AL and NL skin sections. Representative illustration of AL section co-stained with antibodies against CD80 and CD68 (a), CD209 and CD68 (b), and CD163 and CD68 (c). Scale bar 50 µm. High magnification images of one cell below show CD80, CD209 or CD163 expression in red (left), CD68 in green (middle) and co-expression in merge images (right). Scale Bar 20 µm. Boxplots show the quantifications of the number of cells co-expressing CD80 and CD68 (d), CD209 and CD68 (e), and CD163 and CD68 (f) in the dermis of AL and NL, for the European (n = 14) and Japanese volunteers (n = 8). Statistic comparisons between NL and AL groups were carried out using paired Wilcoxon signed ranks test: ***p < 0.001; ns: non-significant difference. Pie charts represent the proportion of CD80+/CD68+ cells (g), CD209+/CD68+ cells (h) and CD163+/CD68+ cells (i) within the total CD68+ macrophages, expressed in %, in NL and AL (combined results of the European and Japanese studies). Nb: a fraction of CD68+ cells may co-express CD209 and CD163. They would be therefore reported in the two pies (h,i), explaining why the sum of the subset percentages appears superior to 100% (see results section). The results show the presence of the three macrophage subsets in AL and NL with an increase of CD80+/CD68+ cells in AL versus NL but no modulation of the two other subsets.
Figure 3
Figure 3
A pro-inflammatory loop sustains a chronic inflammation in actinic lentigines. The activation of pro-inflammatory pathways and the secretion of chemokines, prostaglandins and plasmin, as a consequence of the upregulation (red) or downregulation (green) of a large set of genes, may lead to the observed infiltration and activation of immune cells, CD4+ T-cells and pro-inflammatory M1 macrophages. In turn, these cells, notably M1 macrophages, secreting cytokines, reactive species and proteolytic enzymes, may have a deleterious impact on the skin cells and structure within the lesion. An inflammatory vicious circle thus takes place and leads to a chronic inflammation in actinic lentigines.
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