By protecting against cutaneous inflammation, epidermal pigmentation provided an additional advantage for ancestral humans

Abstract

Pigmentation evolved in ancestral humans to protect against toxic, ultraviolet B irradiation, but the question remains: "what is being protected?" Because humans with dark pigmentation display a suite of superior epidermal functions in comparison with their more lightly pigmented counterparts, we hypothesized and provided evidence that dark pigmentation evolved in Africa to support cutaneous function. Because our prior clinical studies also showed that a restoration of a competent barrier dampens cutaneous inflammation, we hypothesized that resistance to inflammation could have provided pigmented hominins with yet another, important evolutionary benefit. We addressed this issue here in two closely related strains of hairless mice, endowed with either moderate (Skh2/J) or absent (Skh1) pigmentation. In these models, we showed that (a) pigmented mice display a markedly reduced propensity to develop inflammation after challenges with either a topical irritant or allergen in comparison with their nonpigmented counterparts; (b) visible and histologic evidence of inflammation was paralleled by reduced levels of pro-inflammatory cytokines (i.e., IL-1α and INFα); (c) because depigmentation of Skh2/J mouse skin enhanced both visible inflammation and pro-inflammatory cytokine levels after comparable pro-inflammatory challenges, the reduced propensity to develop inflammation was directly linked to the presence of pigmentation; and (d) furthermore, in accordance with our prior work showing that pigment production endows benefits by reducing the surface pH of skin, acidification of albino (Skh1) mouse skin also protected against inflammation, and equalized cytokine levels to those found in pigmented skin. In summary, pigmentation yields a reduced propensity to develop inflammation, consistent with our hypothesis that dark pigmentation evolved in ancestral humans to provide a suite of barrier-linked benefits that now include resistance to inflammation.

Keywords: barrier function; epidermis; evolution; inflammation; melanin; pH; pigmentation.

Figure 1

Pigmentation increases inflammatory thresholds. Irritant (ICD) and atopic dermatitis (AD)‐like inflammation were induced by repeated topical applications of TPA and oxazolone (Ox), respectively, as detailed in Methods. Figure 1a depicts mice treated with TPA, while Figure 1b shows mice treated repeatedly with Ox. Figure 1c & d presents changes in TEWL levels and stratum corneum hydration, respectively, in pigmented (Skh2/J) versus nonpigmented (Skh1) mice. Unpaired two‐tailed t test was used to determine the significance between the two groups. p values (Skh1 vs. Skh2 mice) are indicated as “a” and “b” in Figure 1c and d. N = 10 for mice treated with TPA; N = 11 for Skh1 mice treated with Ox; N = 16 for Skh2/J mice treated with Ox

Figure 2

Depigmentation Decreases Inflammatory Thresholds in Pigmented Mice with Irritant Contact Dermatitis (ICD). Figure 2a displays visible changes in inflammation in depigmented Skh2/J in comparison with Skh1 mice. Figure 2b shows epidermal melanin content in TPA‐treated Skh2/J mice, with or without prior depigmentation with topical hydroquinone (HQ). Data are expressed as % of normal Skh2/J mice (setting normal control as 100%, shown in dotted line). Figure 2c compares levels of epidermal TNFα and IL‐1α protein before and after depigmentation with HQ. Expression levels were normalized to respective normal controls, setting normal controls as 1. Data are expressed as fold‐changes from respective normal controls (shown in dotted lines). Figure 2d exhibits changes in epidermal TNFα and IL‐1α mRNA levels after depigmentation. Data are expressed as % of normal controls (shown in dotted lines). One‐way ANOVA with Tukey's multiple comparison test was used to determine the statistical significances among groups. For Figure 2b, unpaired two‐tailed t test was also used to determine the significance between the two groups. p, F, and t values are indicated in the figures. N = 5 for all groups

Figure 3

Depigmentation Decreases Inflammatory Thresholds in Pigmented Mice with Atopic Dermatitis (AD). Figure 3a displays macroscopic changes in depigmented Skh2/J mice after hapten (Ox) challenges. Figure 3b shows differences in epidermal melanin content in oxazolone (Ox)‐treated Skh2/J mice, with or without topical applications of hydroquinone (HQ). Data are expressed as % of normal Skh2/J mice (setting normal control as 100%, shown in dotted line). Figure 3c displays changes in epidermal TNFα and IL‐1α protein levels. Expression levels were normalized to respective normal controls, setting normal controls as 1. Data are expressed as fold‐changes from respective normal controls (shown in dotted lines). Figure 3d exhibits changes in epidermal TNFα and IL‐1α mRNA levels. Data are expressed as % of normal controls (shown in dotted lines). One‐way ANOVA with Tukey's multiple comparison test was used to determine the statistical significances among groups. For Figure 3b, unpaired two‐tailed t test was also used to determine the significance between the two groups. p, F, and t values are indicated in the figures. N = 6 for all groups

Figure 4

Acidification of Stratum Corneum Increases Inflammatory Thresholds in Depigmented Skh2/J Mice with Irritant Contact Dermatitis (ICD). Figure 4a displays visible changes in inflammation in Skh2/J mice after depigmentation ± acidification with lactobionic acid (LBA). Figure 4b shows differences in skin surface pH after various treatments. Figure 4c displays changes in levels of epidermal TNFα and IL‐1α mRNA levels after depigmentation ± acidification with LBA. Data are expressed as % of control Skh2/J mice, setting controls as 100% shown in dotted line. Figure 4d compares levels of epidermal TNFα and IL‐1α protein after various treatments. Data are expressed as fold‐changes from untreated Skh2/J mice, setting controls as 1 shown in dotted line. One‐way ANOVA with Tukey's multiple comparison test was used to determine the statistical significances among groups. p, F, and t values are indicated in the figures. N = 5 for all groups

Figure 5

Acidification of Stratum Corneum Increases Inflammatory Thresholds in Depigmented Skh2/J Mice with Atopic Dermatitis (AD). Figure 5a displays visible changes in Skh2/J mice after treatments as in Figure 4, plus repeated hapten (Ox) applications Figure 5b shows differences in skin surface pH. Figure 5c displays differences in epidermal TNFα and IL‐1α mRNA levels. Data are expressed as % of control Skh2/J mice, setting controls as 100% shown in dotted line. Figure 5d exhibits changes in epidermal TNFα and IL‐1α protein levels. Data are expressed as fold‐changes for normal Skh2/J mice, setting controls as 1 shown in dotted line. One‐way ANOVA with Tukey's multiple comparison test was used to determine the statistical significances among groups. p, F, and t values are indicated in the figures. N = 7 for all groups, except for Skh2/J + Ox +Veh (N = 6)