Contributed equally
The occurrence of hyperpigmentation or hypopigmentation after inflammation is a common condition in dermatology and cosmetology. Since the exact mechanism of its occurrence is not yet known, prevention and treatment are troublesome. Previous studies have confirmed that α-melanocyte-stimulating hormone, stem cell factor and other factors can promote melanogenesis-related gene expression through the activation of signaling pathways. Recent studies have revealed that a variety of inflammatory mediators can also participate in the regulation of melanogenesis in melanocytes. In this review, we summarized that interleukin-18, interleukin-33, granulocyte-macrophage colony stimulating factor, interferon-γ, prostaglandin E2 have the effect of promoting melanogenesis, while interleukin-1, interleukin-4, interleukin-6, interleukin-17 and tumor necrosis factor can inhibit melanogenesis. Further studies have found that these inflammatory factors may activate or inhibit melanogenesis-related signaling pathways (such as protein kinase A and mitogen activated protein kinase) by binding to corresponding receptors, thereby promoting or inhibiting the expression of melanogenesis-related genes and regulating skin pigmentation processes. This suggests that the development of drugs or treatment methods from the perspective of regulating inflammation can provide new ideas and new targets for the treatment of pigmented dermatosis. This review outlines the current understanding of the inflammation factors' roles in melanogenesis.
A coordination system has been formed under the interaction of various cells in the skin. For instance, the cutaneous neuron-immune-endocrine system consists of interaction and coordination between keratinocytes, melanocytes and dendritic Langerhans cells in the epidermis and the components of the dermis such as mast cells, macrophages, fibroblasts and nerve cells (
Skin hyperpigmentation or hypopigmentation after inflammation is a clinically common symptom. Various acute or chronic inflammatory skin reactions may cause changes in skin pigmentation (
Melanocytes originate from the ectodermal neural crest, migrate to the mesenchyme as the embryo develops, and then further migrate to the skin, eye uveal, stria vascularis, vestibular organ, endolymphatic sac and pia mater (
Multiple signaling pathways are involved in the regulation of melanogenesis, with the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway being one of the most important signaling pathways (
Skin melanogenesis is affected by the epidermal melanin unit, which is mainly composed of keratinocytes and melanocytes. Many of the paracrine factors secreted by keratinocytes can act on melanocytes to promote or inhibit melanogenesis. For example, IL-18, IL-33, GM-CSF can promote melanogenesis, and TNF, IL-1 and IL-6 can inhibit melanogenesis (
Inflammation is a basic pathological process mainly involving defensive reactions of living tissues with a vascular system in response to the stimulation of various damage factors. The chemical factors involved in mediating inflammatory reactions are called chemical mediators or inflammatory mediators. The inflammatory mediators in the skin are mainly secreted by Th cells, lymphocytes, monocytes-macrophages, dendritic cells, and the like. Th cells are mainly classified as Th1 and Th2 cells (
IL-18 is produced by inflammatory stimuli in Langerhans cells (LC), dendritic cells (DC), Kupffer cells, activated monocytes/macrophages, and keratinocytes in the epidermis (
IL-33 can induce mast cells to produce pro-inflammatory cytokines and chemokines (
In addition, granulocyte-macrophage colony-stimulating factor (GM-CSF) which is produced by mononuclear macrophages, keratinocytes and Th cells, has been revealed to promote melanocyte proliferation and melanin synthesis (
Prostaglandin E2 (PGE2) and PGF2α which are produced by fibroblasts and keratinocytes have been revealed to stimulate dendritic cell formation and activate tyrosinase in melanocytes through their dependence on the cAMP signaling pathway and phospholipase C (PLC) (
As one of the most important endogenous mediators of immunity and inflammation, IFN-γ is also a common secretory cytokine in the skin (
TNF is a homotrimeric cytokine, secreted mainly by monocytes and macrophages, and also by keratinocytes, dendritic cells, Th1, Th17 and Th22. It functions by binding to two different receptors: TNFR1/p55 and TNFR2/p75 (
IL-1 is an important pro-inflammatory cytokine in innate immunity that stimulates the differentiation and function of immune surveillance cells and contributes to increased tumor invasiveness, metastasis, and angiogenesis under chronic inflammatory conditions (
IL-4 is a cytokine mainly secreted by Th2 cells and can also be produced by CD8-positive cytotoxic T cells, basophils, eosinophils, and mast cells in chronic inflammation (
IL-6 is secreted by keratinocytes, epidermal cells, fibroblasts and dermal endothelial cells and is involved in the regulation of various biological responses including immune response, inflammation, hematopoiesis, and tumorigenesis by regulating cell growth, survival, and differentiation (
IL-17 is a pro-inflammatory cytokine produced mainly by Th17 cells, and also by other immune cells, including neutrophils, natural killer cells, mast cells, αβ and γδT cells (
It should be noted that the IFN-γ-related data were acquired from a murine melanoma model (B16F10) and IL-1α-related data were based on observations from porcine skin. Therefore, whether their effects on melanogenesis in human melanocytes are the same still requires confirmation by subsequent experiments.
In clinical practice, various treatments can be effective for post-inflammatory hyperpigmentations and hypopigmentations by influencing inflammatory factors. For example, chloasma is a postinflammatory hyperpigmented disease caused by many factors such as heredity, ultraviolet radiation, pregnancy, hormone therapy, cosmetics, and phototoxic drugs (
Although the causes of vitiligo are not completely clear, inflammation has been revealed to play a role in its pathogenesis (
Studies have revealed that a variety of inflammatory factors can promote or inhibit the melanogenesis of melanocytes through different mechanisms, suggesting that the development of medicine or therapies from the perspective of inflammation regulation can provide new ideas and new targets for the treatment of pigmented dermatosis. It is widely considered that the regulatory network of inflammation is very complex, since all types of inflammatory cells are involved in the activation and release of inflammatory mediators. The imbalance of inflammatory factors related to T-cell subsets plays an important role in the development of various skin diseases, however, the relationship between imbalance or changes of T-cell subsets and melanogenesis has yet to be confirmed by further experiments.
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The present study was supported by the Fundamental Research Funds for the Central Universities of Central South University (no. 2017zzts890), the National Natural Science Foundation of China (no. 81703101) and the Natural Science Foundation of Hunan Province (nos. 2018JJ3788 and 2018JJ3793).
The datasets used during the present study are available from the corresponding author upon reasonable request.
CF and JC designed and wrote the paper. JH and QZ designed and supervised the study. JL, LY, XT, LK, SP, YO, LJ, YD, XZ, SL and YY analyzed and interpreted the data. All authors have read and approved the final manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Not applicable.
Not applicable.
The authors declare that they have no interests.
Different signaling pathways regulating melanogenesis. Upon binding to MCIR and adrenergic receptor respectively, α-MSH and catecholamines activate the PKA pathway by increasing cAMP. Then PKA promotes MITF expression, which controls the expression of melanogenesis-related genes TYR, TRP-1 and TRP-2. Upon binding to ETR and adrenergic receptor respectively, ET-1 and catecholamines activate the PKC pathway to promote the expression of TYR, TRP-1 and TRP-2. Upon binding to c-MET, GM-CSFR, and c-KIT and respectively, HGF, GM-CSF, and SCF activate the MAPK pathway to promote the expression of MITF, which in turn increases the expression of TYR, TRP-1 and TRP-2. In addition, NO in the cytoplasm regulates MITF-driven expression of TYR, TRP-1 and TRP-2 through the guanylate cyclase-cGMP pathway. α-MSH, α-melanocyte-stimulating hormone; MC1R, melanocortin-1 receptor; ET-1, endothelin-1; ETR, ET-receptor; HGF, hepatocyte growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; GM-CSFR, granulocyte macrophage colony-stimulating factor receptor; SCF, stem cell factor; AC, adenylate cyclase; cAMP, 3′5′-cyclic adenosine monophosphate; PKA, protein kinase A; c-GMP, cyclic guanosine monophosphate; IP3/DAG, inositol trisphosphate/diacylglycerol; PKC, protein kinase C; MAPK, mitogen activated protein kinase; TYR, tyrosinase; TRP-1, tyrosinase-related protein-1; TRP-2, tyrosinase-related protein-2.
Keratinocyte-derived factors and fibroblast-derived factors that affect melanogenesis in melanocytes through a paracrine effect. Various factors are identified to stimulate (green arrows) or inhibit (red arrows) melanogenesis in melanocytes. Keratinocytes secret factors such as IL-18, IL-33, GM-CSF, PGE2 and PGF2 to stimulate melanocyte melanogenesis as well as TNF, IL-1α and IL-6 to inhibit melanocyte melanogenesis. Fibroblast-derived factors such as IL-33, PGE2 and PGF2 stimulate melanocyte melanogenesis while TNF and IL-6 inhibit melanocyte melanogenesis. IL-18, interleukin-18; IL-33, interleukin-33; GM-CSF, granulocyte-macrophage colony stimulating factor; PGE2, prostaglandin E2; PGF2, prostaglandin F2; TNF, tumor necrosis factor; IL-1α, interleukin-1α; IL-6, interleukin-6.
Cytokines that inhibit or stimulate melanogenesis. Cytokines such as TNF, IL-17 and IL-1β inhibit melanogenesis by suppressing the PKA or MAPK pathway. While cytokines such as IL-18, IL-33 and GM-CSF stimulate melanogenesis by stimulating the PKA or MAPK pathway. IL-4 stimulates melanogenesis by stimulating the STAT pathway. PGE2, PGF2, IL-1α and IL-6 stimulate melanogenesis through unidentified signaling pathways. TNF, tumor necrosis factor; IL-17, interleukin-17; IL-1β, interleukin-1β; IL-18, interleukin-18; IL-33, interleukin-33; GM-CSF, granulocyte-macrophage colony stimulating factor; IL-4, interleukin-4; PGE2, prostaglandin E2; PGF2, prostaglandin F2; IL-1α, interleukin-1α; IL-6, interleukin-6; PKA, protein kinase A; MAPK, mitogen activated protein kinase; STAT, signal transducer and activator of transcription; TYR, tyrosinase; TRP-1, tyrosinase-related protein-1; TRP-2, tyrosinase-related protein-2.
Inflammatory mediators secreted by various types of cells in the skin.
Cell type | Inflammatory factors |
---|---|
Mononuclear macrophages | INF-γ, TNF, IL-1, GM-CSF, IL-6, IL-8, IL-12, IL-18, IL-10 |
Neutrophils | IL-1β, TNF, IL-6, IL-8, IL-15, IFN-γ |
Th1 cells | IFN-γ, TNF, IL-2, IL-3, GM-CSF |
Th2 cells | IL-4, IL-5, IL-6, IL-10, IL-13, IL-3, GM-CSF |
Th17 cells | IL-17, IL-6, IL-21, IL-22, TNF-α |
Mast cells | TNF, IL-1, IL-4, IL-6, IL-8, IL-10, IL-13, IFN-γ |
Dendritic cells | IL-2, IL-4, IL-5, IL-12, INF-γ |
Keratinocytes | IL-18, TNF, IL-1, GM-CSF, INF-γ, IL-33 |
Melanocytes | INF-β, IL-1, IL-8, IL-10, TNF-α |
Fibroblasts | IL-33, TNF, IL-6, IL-8 |
Th1, T helper 1; IFN-γ, interferon-γ; TNF, tumor necrosis factor; IL, interleukin; GM-CSF, granulocyte-macrophage colony stimulating factor.
Function and mechanisms of inflammatory factors in the regulation of melanogenesis.
Factor | Experimental cells | Effect on melanogenesis | Mechanisms | (Refs.) |
---|---|---|---|---|
IL-18 | Keratinocyte | Promotion | Increasing tyrosinase activity and upregulating TYRP-1 and TYRP-2 expression | ( |
IL-33 | Melanocytes | Promotion | Promoting MITF, TYR, TYRP-1, TYRP-2 expression by activating the p38/MAPK and PKA pathways | ( |
GM-CSF | Melanocytes | Promotion | Promoting melanocyte proliferation and melanin synthesis | ( |
PGE2 and PGF2α | Keratinocytes | Promotion | Stimulating melanocyte dendrite formation through a cAMP-dependent pathway | ( |
IFN-γ | B16F10 | Inhibition | Blocking maturation of melanosome and upregulating STAT1 phosphorylation | ( |
TNF | Melanocytes, primary pooled human keratinocytes | Inhibition | Inhibiting melanin formation through PKA and MAPK signaling pathways in combination with IL-17 | ( |
IL-1α | Primary melanocytes, swine skin | Promotion | Combination of KGF increases melanin deposition | ( |
IL-1β | Melanoma cell lines (LB2259-MEL and CP50-MEL) | Inhibition | Downregulating MITF-M expression through NF-κB and JNK pathways | ( |
IL-4 | Melanocytes | Inhibition | Downregulating the expression of MITF, TYRP-1, TYRP-2 through the JAK2-STAT6 signaling pathway | ( |
IL-6 | Melanocytes | Inhibition | Decreasing tyrosinase activity | ( |
IL-17 | Melanocytes, primary pooled human keratinocytes | Inhibition | Inhibiting melanin formation through PKA and MAPK signaling pathways in combination with TNF | ( |
TYRP-1, tyrosinase-related protein-1; TYRP-2, tyrosinase-related protein-2; MITF, microphthalmia-associated transcription factor; TYR, tyrosinase; PKA, protein kinase A; MAPK, mitogen activated protein kinase; JNK, c-Jun N-terminal kinase; JAK-STAT, Janus kinase-signal transducer and activator of transcription.