It is well accepted that the interaction between the autoantigen : MHC-I complex and the self-reactive TCR on CD8 T cells is weak.

Thus, while self-reactive T cells are present in the periphery, their TCR interactions with peptide-MHC Class I complex are insufficient to mediate activation.

Thus, understanding the mechanisms that regulate NKG2DL expression on stressed melanocytes can lead to development of therapeutic approaches targeting the interactions of NKG2D + self-reactive CD8 T cells with melanocytes in vitiligo.

IFN-gamma is also responsible for stimulating the production of CXCL9 and CXCL10 in keratinocytes , which engages the chemokine receptor CXCR3 on melanocytes and triggers apoptosis , further contributing to the disease ( 127 ) .

In vitiligo , stressed melanocytes increase the expression of Hsp70 , which binds and transports potentially immunogenic antigens to the MHC complex , allowing for their presentation on the cell surface to cytotoxic T cells ( 109 ) .

Of significance, proinflammatory signals such as IFN-alpha and TLR4 and TLR7/8 signaling, as well as the ataxia telangiectasia mutated and Rad3 related (ATM and ATR) DNA damage response pathway also result in surface expression of these ligands.

Interestingly , keratinocytes in vitiligo lesions aberrantly produce IL-1 , IL-6 , and TNF-alpha , which inhibit melanocyte function ( 65 , 66 ) and elicit an inflammatory response .

Interestingly, keratinocytes in vitiligo lesions aberrantly produce IL-1, IL-6, and TNF-alpha, which inhibit melanocyte function and elicit an inflammatory response.

Blockade of IL-15Rbeta (CD122) reduces IFN-gamma production and can eliminate skin T RM and reverse vitiligo.

Blockade of IL-15Rbeta (CD122) reduces IFN-gamma production and can eliminate skin T RM and reverse vitiligo.

Blockade of IL-15Rbeta ( CD122 ) reduces IFN-gamma production and can eliminate skin TRM and reverse vitiligo ( 133 ) .

Blockade of IL-15Rbeta (CD122) reduces IFN-gamma production and can eliminate skin T RM and reverse vitiligo.

Blockade of IL-15Rbeta (CD122) reduces IFN-gamma production and can eliminate skin T RM and reverse vitiligo.

This differentiation is mediated by IL-15 derived from keratinocytes.

Studies show that IFN-gamma directly induces melanocyte apoptosis and its signaling enhances CD8 T cell function and expansion.

Following nuclear translocation, HSF1 binds to the promoter regions of both HSP70i and NKG2DL, initiating their transcription.

Notably, we and others have demonstrated that NKG2D signaling upregulates IFN-gamma production.

In this case , NKG2D enhances TCR activation and thus , T cell function ( 18-20 ) .

In this case, NKG2D enhances TCR activation and thus, T cell function.

NKG2D mediated activation of CD8 T cells may thus play a significant role in the development of vitiligo, as discussed below.

Interestingly, keratinocytes in vitiligo lesions aberrantly produce IL-1, IL-6, and TNF-alpha, which inhibit melanocyte function and elicit an inflammatory response.

ROS production is also increased by TNF-alpha, further promoting stress signals in vitiligo melanocytes.

ROS production is also increased by TNF-alpha , further promoting stress signals in vitiligo melanocytes .

Of significance, proinflammatory signals such as IFN-alpha and TLR4 and TLR7/8 signaling, as well as the ataxia telangiectasia mutated and Rad3 related (ATM and ATR) DNA damage response pathway also result in surface expression of these ligands.

Of significance, proinflammatory signals such as IFN-alpha and TLR4 and TLR7/8 signaling, as well as the ataxia telangiectasia mutated and Rad3 related (ATM and ATR) DNA damage response pathway also result in surface expression of these ligands.

Moreover, free Hsp70 also triggers an immune response by interacting with DC surface receptors, inducing the expression of human NKG2DL MICA.

These events , in combination with reduced suppression by dysfunctional Treg cells , result in the onset , perpetuation , and spreading of vitiligo .

Exposure to UV light and its absorption by melanocytes causes photo oxidation of melanin, generating superoxide radicals, which in turn induce melanin biosynthesis.

Monobenzone induces ROS generation and oxidative stress in the skin, further contributing to the autoimmune response in vitiligo.

High ROS can also induce ER oxidation; in particular, H 2 O 2 can interfere with the ion channel TRPM2, resulting in higher Ca 2+ influx into the cell and the mitochondria.

Exposure to UV light and its absorption by melanocytes causes photo-oxidation of melanin , generating superoxide radicals ( 54 ) , which in turn induce melanin biosynthesis ( 56 ) .

Exposure to UV light and its absorption by melanocytes causes photo oxidation of melanin, generating superoxide radicals, which in turn induce melanin biosynthesis.

Calreticulin , an endoplasmic reticulum ( ER ) protein that regulates Ca2 + homeostasis and signaling , is also modulated by H2O2 , which increases calreticulin expression and translocation to the cell surface of melanocytes .

Calreticulin , an endoplasmic reticulum ( ER ) protein that regulates Ca2 + homeostasis and signaling , is also modulated by H2O2 , which increases calreticulin expression and translocation to the cell surface of melanocytes .

Corroborating this study, a reduction in phosphorylated forms of ERK1/2 and p38 has been reported in an experimental rat model of autoimmune myocarditis study upon treatment with quercetin [ xref ].

An interesting study showed that quercetin and honokiol inhibited cytosolic PLA2 phosphorylation and activation in differentiated SH-SY5Y neuroblastoma cells [ xref ].

Studying various immune cell models (RAW264.7 macrophages and bone marrow-derived macrophages, HMC-1 human mast cells, mouse BV-2 microglia and HUVECs) the inhibitory effects of quercetin on NFκB activation has been reported, including a reduction in nuclear translocation of p50 and p65 subunits, an inhibition of the phosphorylation of IκBα and their consequent degradation, and a blockage of the IKK activation.

For example, quercetin has been shown to interfere with the phosphorylation and activation of JNK on LPS-treated RAW 264.7 macrophages, thus preventing the activator protein 1 (AP-1) from binding to ADN, and inhibiting TNFα transcription [ xref ].

A novel point for cellular control for polyphenols is secondary to their ability to modulate modular epigenetic mechanisms such as DNA methylation, histone modifications and posttranscriptional regulation by microRNAs, modulating the activation and differentiation of immune cells.

SLE represents an AID of epigenetic origin characterized by the deterioration of T-cell DNA methylation.

Epigenetic mechanisms (DNA methylation, histone acetylation, microRNAs), in the influence of environmental factors, affect the prevalence of many AIDs.

Different factors, such as genetic factors (CD25, STAT4), epigenetic factors (DNA methylation, histone modifications) and environmental factors (xenobiotics, drugs, hormones) trigger autoimmunity.

Curcumin has also been reported to reactivate the neprilysin gene (a strong inhibitor of Akt) through CpG demethylation, leading to Akt inhibition and the subsequent inhibition of NFkappaB in mouse neuroblastoma N2a cells [XREF_BIBR].

Curcumin has also been reported to reactivate the neprilysin gene (a strong inhibitor of Akt) through CpG demethylation, leading to Akt inhibition and the subsequent inhibition of NFκB in mouse neuroblastoma N2a cells [ xref ].

In addition , resveratrol as well as oleuropein aglycone and hydroxytyrosol significantly reduce the activation of NFkappaB in LPS-stimulated human umbilical vein endothelial cells ( HUVECs ) as determined by electrophoretic mobility shift assay [ 87 ] .

In addition, resveratrol as well as oleuropein aglycone and hydroxytyrosol significantly reduce the activation of NFkappaB in LPS stimulated human umbilical vein endothelial cells (HUVECs) as determined by electrophoretic mobility shift assay [XREF_BIBR].

In addition, resveratrol as well as oleuropein aglycone and hydroxytyrosol significantly reduce the activation of NFkappaB in LPS stimulated human umbilical vein endothelial cells (HUVECs) as determined by electrophoretic mobility shift assay [XREF_BIBR].

EGCG has been shown to reduce the activity of NFkappaB via hypoacetylation of p65 by inhibiting the activity of histone acetyl transferase [XREF_BIBR, XREF_BIBR].

Curcumin has also been reported to reactivate the neprilysin gene (a strong inhibitor of Akt) through CpG demethylation, leading to Akt inhibition and the subsequent inhibition of NFkappaB in mouse neuroblastoma N2a cells [XREF_BIBR].

Genistein has been shown to reduce the overproduction of TNFalpha and IL-6 in RAW 264.7 macrophages stimulated by LPS via inhibition of NFkappaB activation [XREF_BIBR].

Genistein has been shown to reduce the overproduction of TNFalpha and IL-6 in RAW 264.7 macrophages stimulated by LPS via inhibition of NFkappaB activation [XREF_BIBR].

In addition , resveratrol as well as oleuropein aglycone and hydroxytyrosol significantly reduce the activation of NFkappaB in LPS-stimulated human umbilical vein endothelial cells ( HUVECs ) as determined by electrophoretic mobility shift assay [ 87 ] .

Resveratrol treatment inhibited p38 and JNK signalling pathways in IL-1beta-stimulated rat RSC-364 synovial cells and in HUVECs treated with hydrogen peroxide [XREF_BIBR, XREF_BIBR].

In addition, resveratrol as well as oleuropein aglycone and hydroxytyrosol significantly reduce the activation of NFkappaB in LPS stimulated human umbilical vein endothelial cells (HUVECs) as determined by electrophoretic mobility shift assay [XREF_BIBR].

Resveratrol blocks the activation of NF-kappaB in macrophage RAW 264.7 cells when stimulated with LPS through avoiding IKK activation and IkappaB phosphorylation [XREF_BIBR].

Resveratrol treatment inhibited p38 and JNK signalling pathways in IL-1beta-stimulated rat RSC-364 synovial cells and in HUVECs treated with hydrogen peroxide [XREF_BIBR, XREF_BIBR].

In addition, resveratrol as well as oleuropein aglycone and hydroxytyrosol significantly reduce the activation of NFkappaB in LPS stimulated human umbilical vein endothelial cells (HUVECs) as determined by electrophoretic mobility shift assay [XREF_BIBR].

Similarly , other polyphenols , such as luteolin , chrysin , hesperidin , naringin and kaempferol have been shown to reduce inflammation by interfering with MAPKs pathways [ 107-109 ] .

Quercetin, a flavonoid class of polyphenolic compound was tested for its beneficial effect to reduce oxidative stress and inflammation in sarcoidosis.

In addition , resveratrol as well as oleuropein aglycone and hydroxytyrosol significantly reduce the activation of NFkappaB in LPS-stimulated human umbilical vein endothelial cells ( HUVECs ) as determined by electrophoretic mobility shift assay [ 87 ] .

EGCG also prevented the IKK activation and inhibited phosphorylation of the p65 subunit of NFkappaB in a human respiratory epithelium A549 cells stimulated by IL-1beta [XREF_BIBR].

An interesting study showed that quercetin and honokiol inhibited cytosolic PLA2 phosphorylation and activation in differentiated SH-SY5Y neuroblastoma cells [XREF_BIBR].

Quercetin suppressed the phosphorylation of Akt by direct binding and inhibition of PI3K in JB6 mouse epidermal cells [XREF_BIBR].

EGCG inhibited epithelial-mesenchymal transition and inflammation via the PI3K and AKT pathway by upregulating the expression of phosphatase and tensin homolog (PTEN).

Curcumin has been found to upregulate the expression of miR-181b, which, in turn, reduces the expression of the pro inflammatory chemokines CXCL1 and CXCL2 [XREF_BIBR].

Curcumin has been found to upregulate the expression of miR-181b, which, in turn, reduces the expression of the pro inflammatory chemokines CXCL1 and CXCL2 [XREF_BIBR].

The expression of the pro inflammatory cytokine IL-17 was reduced by resveratrol treatment in cardiac fibroblasts in a process mediated by PI3K and Akt inhibition [XREF_BIBR].

Resveratrol has been shown to decrease miR-21 expression and NFkappaB activity in U251 brain tumour cells [XREF_BIBR].

Considering PLA 2 as the first enzyme in the AA cascade, it has been evidenced the inhibitory capabilities by polyphenols such as quercetin, kaempferol, and galangin, as well as some anthocyanidins (cyanidin, delphinidin malvidin, peonidin and petunidin) [ xref – xref ] Catechol (1,2-dihydroxybenzen) binds to PLA2 preventing the substrate from entering into the active site [ xref ].

Polyphenols in the treatment of autoimmune diseases In addition to protecting body from infections and diseases , the immune system produces auto-antibodies that can cause complex autoimmune disorders , such as Type I diabetes , primary biliary cirrhosis , rheumatoid arthritis , and multiple sclerosis , to name a few .

However , under certain circumstances , the immune system may produce auto-antibodies against its own cells , leading to autoimmune diseases .

This effect seems to be initially mediated by the inhibition of the IRAK (IL-1beta-mediated IL-1beta receptor associated kinase) degradation, which prevents IKK activation.

EGCG has been shown to reduce the activity of NFkappaB via hypoacetylation of p65 by inhibiting the activity of histone acetyl transferase [XREF_BIBR, XREF_BIBR].

EGCG has been shown to reduce the activity of NFkappaB via hypoacetylation of p65 by inhibiting the activity of histone acetyl transferase [XREF_BIBR, XREF_BIBR].

Curcumin has also been reported to reactivate the neprilysin gene (a strong inhibitor of Akt) through CpG demethylation, leading to Akt inhibition and the subsequent inhibition of NFkappaB in mouse neuroblastoma N2a cells [XREF_BIBR].

Curcumin has also been reported to reactivate the neprilysin gene ( a strong inhibitor of Akt ) through CpG demethylation , leading to Akt inhibition and the subsequent inhibition of NFkappaB in mouse neuroblastoma N2a cells [ 132 ] .

Also , resveratrol induced neuroprotection in rats undergoing ischemia / reperfusion induced cerebral damage by activating the PI3K / Akt survival pathway [ 119 ] .

Among the various polyphenols , resveratrol has been shown to be a strong activator of SIRT1 , resulting in the inhibition of NFkappaB and its downstream genes , such as COX-2 and iNOS [ 123 , 124 ] .

Polyphenols activate intracellular pathways such as arachidonic acid dependent pathway, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathway, mitogen-activated protein kinases (MAPKs) pathway, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway and epigenetic modulation, which regulate the host’s immune response.

In addition, several other polyphenols, such as quercetin, curcumin, myricetin and fisetin also activate SIRT1 [ xref – xref ].

Once in the cytoplasm , AA is targeted by various enzymes such as COX and LOX to generate prostaglandins ( PGs ) and thromboxanes A2 or hydroxyeicosatetraenoic acids ( HETEs ) and leukotrienes ( LTs ) , respectively [ 69 ] .

Epigenetic mechanisms (DNA methylation, histone acetylation, microRNAs), in the influence of environmental factors, affect the prevalence of many AIDs.

The retention of tissue-resident memory T cells is mediated by TGF-beta , which up-regulates CD103 expression and down-regulates CCR7 expression .

Similarly, CD8 + T cells lacking CCR10 impaired their T RM forming capacity.

Apart from maintenance property, IL-15 strongly induces perforin and granzyme B expression in CD8 + CD103 + CD49a + T RM cells but not in CD8 + CD103 + CD49a - T RM cells isolated from normal human skin.

Apart from maintenance property, IL-15 strongly induces perforin and granzyme B expression in CD8 + CD103 + CD49a + T RM cells but not in CD8 + CD103 + CD49a - T RM cells isolated from normal human skin.

The retention of tissue-residentmemoryT cells is mediated by TGF-beta, which up-regulates CD103 expression and down-regulates CCR7 expression.

TGF-beta induces CD103 expression on activated CD8 + T cells, but not CD4 + T cells, and leads to CD103 mediated adhesion of CD8 + T cells, but not CD4 + T cells, to monolayer human keratinocyte cultures.

However, another study showed that TGF-beta also induces CD103 expression on CD4 + T cells and mediates cell adhesion to keratinocyte.

IL-12 and TGF-beta can upregulate CD49a expression on CD8 + T cells.

IL-12 and TGF-beta can upregulate CD49a expression on CD8 + T cells.

Since IL-12 can induce IFN-gamma production and CD49a expression, it is tempting to speculate that in the psoriasis context, IL-17A-producing T RM cells, which preferentially express IL-23R, downregulate their CD49a due to a greater influence of IL-23 over IL-12.

Similarly, CD8 + T RM cells in the skin also increase the expression of FABP4 and FABP5.

Similarly, CD8 + T RM cells in the skin also increase the expression of FABP4 and FABP5.

Similarly, CD8 + T RM cells in the skin also increase the expression of FABP4 and FABP5.

Similarly, CD8 + T RM cells in the skin also increase the expression of FABP4 and FABP5.

The ligand for CCR8, CCL1, is preferentially expressed in human skin, and keratinocyte derived prostaglandin E 2 and vitamin D3 can induce CCR8 expression by CD8 + T cells, suggesting that it may involve in T RM localization in skin.

In contrast, thexenografting model with human skin showed that CD4 + CLA + CD103 + T RM cells down-regulate CD69 expression, exit from the skin, and reach into the circulation.

In contrast, thexenografting model with human skin showed that CD4 + CLA + CD103 + T RM cells down-regulate CD69 expression, exit from the skin, and reach into the circulation.

The retention of tissue-residentmemoryT cells is mediated by TGF-beta, which up-regulates CD103 expression and down-regulates CCR7 expression.

High-fat diet upregulated E-FABP expression and promote skin inflammation , suggesting the role of lipid metabolism in immune regulation ( 105 ) .

High-fat diet upregulated E-FABP expression and promote skin inflammation , suggesting the role of lipid metabolism in immune regulation ( 105 ) .

Endothelial cells increase the expression of adhesion molecules ; CD54 ( ICAM-1 ) and CD106 ( VCAM-1 ) , which guide T cell entry into the tissue .

These mediators stimulate keratinocytes to produce TNF-alpha , IL-8 , and vascular endothelial growth factor , thereby promoting inflammation , neutrophil recruitment , and angiogenesis ( 129 ) .

These mediators stimulate keratinocytes to produce TNF-alpha , IL-8 , and vascular endothelial growth factor , thereby promoting inflammation , neutrophil recruitment , and angiogenesis ( 129 ) .

These mediators stimulate keratinocytes to produce TNF-alpha , IL-8 , and vascular endothelial growth factor , thereby promoting inflammation , neutrophil recruitment , and angiogenesis ( 129 ) .

Thus , CD8 + CD103 + TRM cells efficiently produce IL-17A .

Upon stimulation of the skin of psoriasis patients, the CD8 + CD103 + CD49a - T RM cells in the epidermis seem to be reactivated and initiate IL-17A production.

In the ex vivo expanded T cells, certain populations of CD8 + CD103 + T cells produce IFN- gamma, IL-17A or IL-22, while CD4 + CD103 + T cells scarcely elaborate these cytokines.

In the ex vivo expanded T cells, certain populations of CD8 + CD103 + T cells produce IFN- gamma, IL-17A or IL-22, while CD4 + CD103 + T cells scarcely elaborate these cytokines.

TGF-beta induces CD103 expression on activated CD8 + T cells, but not CD4 + T cells, and leads to CD103 mediated adhesion of CD8 + T cells, but not CD4 + T cells, to monolayer human keratinocyte cultures.

In the ex vivo expanded T cells, certain populations of CD8 + CD103 + T cells produce IFN- gamma, IL-17A or IL-22, while CD4 + CD103 + T cells scarcely elaborate these cytokines.

CD103 on CD8 T RM cells mediate cell adhesion to the epidermis and thus promote local retention.

TGF-beta induces CD103 expression on activated CD8 + T cells, but not CD4 + T cells, and leads to CD103 mediated adhesion of CD8 + T cells, but not CD4 + T cells, to monolayer human keratinocyte cultures.

However, another study showed that TGF-beta also induces CD103 expression on CD4 + T cells and mediates cell adhesion to keratinocyte.

TGF-beta induces CD103 expression on activated CD8 + T cells, but not CD4 + T cells, and leads to CD103 mediated adhesion of CD8 + T cells, but not CD4 + T cells, to monolayer human keratinocyte cultures.

In contrast , in the xenotransplantation model of psoriasis , blocking CD49a inhibits T cell migration into the epidermis , resulting in a decrease of TRM cells and prevention of psoriasis development ( 76 ) .

Th17-derived cytokines , IL-17A , IL-17F and IL-22 , induce epidermal acanthosis , which represents an intriguing histological finding of psoriasis and results from the proliferation of epidermal keratinocytes .

Basically, IL-15 promotes proliferation and survival of circulating memory CD8 + T cells but did not affect regulatory T cell populations in human.

They sense autoantigen in the skin long after stabilization of disease and produce IFN-gamma, which further induces CXCL9, and CXCL10 production.

CD4 + T cells producing interleukin (IL)-17, named Th17 cells, play an essential role in its pathogenesis.

Th17-derived cytokines , IL-17A , IL-17F and IL-22 , induce epidermal acanthosis , which represents an intriguing histological finding of psoriasis and results from the proliferation of epidermal keratinocytes .

Th17-derived cytokines , IL-17A , IL-17F and IL-22 , induce epidermal acanthosis , which represents an intriguing histological finding of psoriasis and results from the proliferation of epidermal keratinocytes .

They sense autoantigen in the skin long after stabilization of disease and produce IFN-gamma, which further induces CXCL9, and CXCL10 production.

They sense autoantigen in the skin long after stabilization of disease and produce IFN-gamma , which further induces CXCL9 , and CXCL10 production .

TGF-beta induces CD103 expression on activated CD8 + T cells , but not CD4 + T cells , and leads to CD103-mediated adhesion of CD8 + T cells , but not CD4 + T cells , to monolayer human keratinocyte cultures ( 68 ) .

The retention of tissue-resident memory T cells is mediated by TGF-beta , which up-regulates CD103 expression and down-regulates CCR7 expression .

Since IL-12 can induce IFN-gamma production and CD49a expression , it is tempting to speculate that in the psoriasis context , IL-17A-producing TRM cells , which preferentially express IL-23R ( 74 ) , downregulate their CD49a due to a greater influence of IL-23 over IL-12 .

Since IL-12 can induce IFN-gamma production and CD49a expression , it is tempting to speculate that in the psoriasis context , IL-17A-producing TRM cells , which preferentially express IL-23R ( 74 ) , downregulate their CD49a due to a greater influence of IL-23 over IL-12 .

Thus, CD8 + CD103 + T RM cells efficiently produce IL-17A.

Thus , CD8 + CD103 + TRM cells efficiently produce IL-17A .

Upon stimulation of the skin of psoriasis patients, the CD8 + CD103 + CD49a - T RM cells in the epidermis seem to be reactivated and initiate IL-17A production.

In the ex vivo expanded T cells, certain populations of CD8 + CD103 + T cells produce IFN- gamma, IL-17A or IL-22, while CD4 + CD103 + T cells scarcely elaborate these cytokines.

In the ex vivo expanded T cells, certain populations of CD8 + CD103 + T cells produce IFN- gamma, IL-17A or IL-22, while CD4 + CD103 + T cells scarcely elaborate these cytokines.

CD103 + T RM cells produce IFN-gamma, IL-17A, and IL-22.

In CD8 + T cells, CD103 + T RM cells more frequently produce IL-17A than CD103 - T cells.

Thus, CD8 + CD103 + T RM cells efficiently produce IL-17A.

T RM cells producing IL-17A in resolved psoriasis epidermis could be associated with early relapse, and CD8 + T RM cells with IL-17A-producing potential in disease-naive, non lesional sites possibly correlate with disease duration.

CD103 + T RM cells produce IFN-gamma, IL-17A, and IL-22.

T RM cells producing IL-17A in resolved psoriasis epidermis could be associated with early relapse, and CD8 + T RM cells with IL-17A-producing potential in disease-naive, non lesional sites possibly correlate with disease duration.

The ligand for CCR8 , CCL1 , is preferentially expressed in human skin , and keratinocyte-derived prostaglandin E2 and vitamin D3 can induce CCR8 expression by CD8 + T cells , suggesting that it may involve in TRM localization in skin ( 62 , 63 ) .

Knockout of TGF-β receptor 2 in hair follicle melanocyte lineage blocks the Smad2 phosphorylation, resulting in a loss of quiescence state of McSCs.

TGF-β binds TGF-β receptors in melanocytes, leading to the phosphorylation of downstream effector Smad2, which inhibits melanocyte growth and melanogenesis through downregulating PAX3 and MITF transcription xref , xref .

On the contrary, when agouti activity is inhibited by beta-Defensin, or Corin, or beta-catenin in the DP, the yellow coat turns to be black XREF_BIBR - XREF_BIBR.

Conditional knockout of NFIB in HFSCs promotes McSCs proliferation and differentiation, indicating a role of NFIB as a regulator of McSC behavior 73.

Conditional knockout of NFIB in HFSCs promotes McSCs proliferation and differentiation, indicating a role of NFIB as a regulator of McSC behavior 73.

On the contrary, when agouti activity is inhibited by beta-Defensin, or Corin, or beta-catenin in the DP, the yellow coat turns to be black XREF_BIBR - XREF_BIBR.

On the contrary, when agouti activity is inhibited by beta-Defensin, or Corin, or beta-catenin in the DP, the yellow coat turns to be black XREF_BIBR - XREF_BIBR.

On the contrary, when agouti activity is inhibited by beta-Defensin, or Corin, or beta-catenin in the DP, the yellow coat turns to be black XREF_BIBR - XREF_BIBR.

Mechanistically, knockout of Kindlin-1 promotes cutaneous epithelial stem cells differentiation via inhibiting alpha (v) beta (6) integrin mediated TGF-beta1 liberation and promoting integrin independent Wnt ligand expression to activate Wnt and beta-catenin signaling 82.

Mechanistically, knockout of Kindlin-1 promotes cutaneous epithelial stem cells differentiation via inhibiting alpha (v) beta (6) integrin mediated TGF-beta1 liberation and promoting integrin independent Wnt ligand expression to activate Wnt and beta-catenin signaling 82.

Mechanistically, knockout of Kindlin-1 promotes cutaneous epithelial stem cells differentiation via inhibiting alpha (v) beta (6) integrin mediated TGF-beta1 liberation and promoting integrin independent Wnt ligand expression to activate Wnt and beta-catenin signaling 82.

Inhibition of Wnt signaling by a Wnt antagonist secreted frizzled-related protein 4 (sFRP4), which is exclusively expressed in the epithelial cells but not the melanocytes of the hair follicle, results in a decrease of melanocytes differentiation in the regenerating hair follicle xref .

Even the melanocyte progenitors emigrate into feathers, the differentiation may be suppressed by agouti, made by the peripheral pulp fibroblasts 1.

Pax3 not only promotes melanogenesis by activating the expression of MITF, but also maintains McSCs quiescence by competing with MITF through binding an enhancer responsible for the expression of dopachrome tautomerase (DCT), an intermediate in the biosynthesis of melanin.

Alx3 decreases melanin production by directly suppressing the expression of MITF, by indirectly inhibiting the secretion of Edn3, and by indirectly promoting the expression of ASIP.

Sox10, Pax3, and Wnt3a mediated Wnt and beta-catenin signaling induce the transcription of MITF and promote differentiation of neural crest into melanoblasts XREF_BIBR - XREF_BIBR, though MITF is not expressed in the neural crest.

Inhibition of NFIB signaling in HFSCs directly stimulates expression of endothelin 2 (Edn2), which is required in HFSCs dependent McSCs activation.

For example, MITF dependent expression of microRNA-211 promotes pigmentation in melanoblast and melanocyte cell lines by inhibiting the expression of TGF-beta receptor 2, which is involved in the maintenance of McSCs quiescence.

Alx3 decreases melanin production by directly suppressing the expression of MITF, by indirectly inhibiting the secretion of Edn3, and by indirectly promoting the expression of ASIP.

For example, MITF dependent expression of microRNA-211 promotes pigmentation in melanoblast and melanocyte cell lines by inhibiting the expression of TGF-beta receptor 2, which is involved in the maintenance of McSCs quiescence.

For example, MITF dependent expression of microRNA-211 promotes pigmentation in melanoblast and melanocyte cell lines by inhibiting the expression of TGF-beta receptor 2, which is involved in the maintenance of McSCs quiescence.

Through interacting with PAX3, FOXD3 prevents binding of PAX3 to MITF promoter to repress melanogenesis in zebrafish, quail and chick neural crest cells XREF_BIBR, XREF_BIBR, suggesting that down-regulation of Foxd3 is a crucial step during the early phase of melanoblast lineage specification from neural crest cells.

Through interacting with PAX3, FOXD3 prevents binding of PAX3 to MITF promoter to repress melanogenesis in zebrafish, quail and chick neural crest cells xref , xref , suggesting that down-regulation of Foxd3 is a crucial step during the early phase of melanoblast lineage specification from neural crest cells.

In human melanoma cells, MITF also interacts directly with beta-catenin and redirects beta-catenin transcriptional activity away from target genes regulated by Wnt and beta-catenin signaling, toward MITF specific target promoters to activate transcription 57.

In human melanoma cells, MITF also interacts directly with β-catenin and redirects β-catenin transcriptional activity away from target genes regulated by Wnt/β-catenin signaling, toward MITF-specific target promoters to activate transcription xref .

TGF-β binds TGF-β receptors in melanocytes, leading to the phosphorylation of downstream effector Smad2, which inhibits melanocyte growth and melanogenesis through downregulating PAX3 and MITF transcription xref , xref .

TGF-beta binds TGF-beta receptors in melanocytes, leading to the phosphorylation of downstream effector Smad2, which inhibits melanocyte growth and melanogenesis through downregulating PAX3 and MITF transcription XREF_BIBR, XREF_BIBR.

Notch ligands including Jagged1, Jagged2, Delta-like1, Delta-like3 and Delta-like4 bind to Notch receptor, which induces signal transduction cascade through the induction of transcription factor RBP-JK to initiate the transcription of target genes 69.

UV and ionizing radiation induced DNA damage triggers McSC differentiation, leading to McSC exhaustion and hair graying XREF_BIBR, XREF_BIBR, XREF_BIBR.

Although alpha-MSH can derive from epithelial cells and systematically, the activation of Mc1r signaling by alpha-MSH is in the DP, which further regulates melanocyte pigmentation.

These data indicate that MITF may enhance the role of Wnt and beta-catenin signaling in proliferation and differentiation of McSCs in a feedback mechanism.

Sox10, Pax3, and Wnt3a mediated Wnt and beta-catenin signaling induce the transcription of MITF and promote differentiation of neural crest into melanoblasts XREF_BIBR - XREF_BIBR, though MITF is not expressed in the neural crest.

These data indicate that MITF may enhance the role of Wnt and beta-catenin signaling in proliferation and differentiation of McSCs in a feedback mechanism.

HGF, SCF, and End3 have been revealed to promote melanoblast or melanocyte proliferation and differentiation XREF_BIBR, XREF_BIBR.

HGF, SCF, and End3 have been revealed to promote melanoblast or melanocyte proliferation and differentiation XREF_BIBR, XREF_BIBR.

HGF, SCF, and End3 have been revealed to promote melanoblast or melanocyte proliferation and differentiation XREF_BIBR, XREF_BIBR.

HGF, SCF, and End3 have been revealed to promote melanoblast or melanocyte proliferation and differentiation XREF_BIBR, XREF_BIBR.

Continuous activation of beta-catenin Signaling in McSCs promotes McSCs differentiation, exhaustion and premature hair graying 8.

In human melanoma cells, MITF also interacts directly with beta-catenin and redirects beta-catenin transcriptional activity away from target genes regulated by Wnt and beta-catenin signaling, toward MITF specific target promoters to activate transcription 57.

Sox10, Pax3, and Wnt3a mediated Wnt and beta-catenin signaling induce the transcription of MITF and promote differentiation of neural crest into melanoblasts XREF_BIBR - XREF_BIBR, though MITF is not expressed in the neural crest.

Inhibition of Wnt signaling by a Wnt antagonist secreted frizzled related protein 4 (sFRP4), which is exclusively expressed in the epithelial cells but not the melanocytes of the hair follicle, results in a decrease of melanocytes differentiation in the regenerating hair follicle 79.

PDGF promotes the proliferation of human melanoblasts and differentiation of melanocytes 104, indicating that adipose secreted PDGF may also regulate McSCs activation and differentiation.

Mechanistically, knockout of Kindlin-1 promotes cutaneous epithelial stem cells differentiation via inhibiting alpha (v) beta (6) integrin mediated TGF-beta1 liberation and promoting integrin independent Wnt ligand expression to activate Wnt and beta-catenin signaling 82.

Injecting Wnt inhibitor DKK1 into skin inhibits TPA induced the proliferation and differentiation of McSCs 52.

Injecting Wnt inhibitor DKK1 into skin inhibits TPA induced the proliferation and differentiation of McSCs 52.

So the white color can be due to the absence of melanocytes by non migration or death of melanocytes, or due to the suppression of differentiation by agouti or other inhibitors.

HGF, SCF, and End3 have been revealed to promote melanoblast or melanocyte proliferation and differentiation XREF_BIBR, XREF_BIBR.

HGF, SCF, and End3 have been revealed to promote melanoblast or melanocyte proliferation and differentiation XREF_BIBR, XREF_BIBR.

This is attributable at least in part to TRPV4 function in keratinocytes, where calcium influx through this channel triggers ERK phosphorylation.

The absence of TRPA1 has also been shown to reduce scratching behaviors in the acetone-ether-water mouse model of dry skin and chronic itch [XREF_BIBR].

Consistent with this observation, IL31 receptors were found to be colocalized with both TRPA1 and TRPV1 in sensory neurons, and genetic elimination of either channel reduced IL31 induced itch [XREF_BIBR].

These authors showed that application of the TRPV3 agonists eugenol or 2-APB to either cultured human hair follicles or outer root sheath (ORS) keratinocytes, produced a dose dependent suppression of proliferation and induction of apoptosis in both systems.

It has also been reported that either chemical or thermal TRPM8 activation can reduce PGE2 release from human keratinocytes in response to UVB irradiation [XREF_BIBR].

In organ cultures of these hair follicles, activation of TRPV1 suppressed epithelial proliferation and hair shaft elongation and promoted hair follicle regression [XREF_BIBR].

Two different stimuli that are known to promote keratinocyte differentiation, elevations in extracellular calcium and 1, 25, dihydroxyvitamin D3, both upregulate transcription of TRPV6 [XREF_BIBR].

In these cells, capsaicin could evoke the release of IL8 and prostaglandin E2 (PGE2) and upregulate the expression of cyclooxygenase 2 (COX2), providing evidence for potential proinflammatory activities.

TRPA1 proline hydroxylation analogously mediates changes in TRPA1 cold sensitivity in response to intracellular oxygen concentrations [ xref ].

Conversely, factors that suppress TRPV3 activity include oxygen dependent hydroxylation of TRPV3 by Factor-inhibiting-hypoxia inducible factor [XREF_BIBR].

Conversely, factors that suppress TRPV3 activity include oxygen-dependent hydroxylation of TRPV3 by Factor-inhibiting-hypoxia inducible factor [ xref ].