The CCL20 and CCR6 axis in psoriasis.

Psoriasis is a TNF-α/IL-23/IL-17A-mediated inflammatory skin disease that causes a significant socioeconomic burden in afflicted patients. IL-17A-producing immune cells, including Th17 cells, are crucial effector cells in the development of psoriasis. IL-17A stimulates epidermal keratinocytes to produce CCL20, which eventually recruits CCR6 + Th17 cells into the lesional skin. Thus, the CCL20/CCR6 axis works as a driving force that prepares an IL-17A-rich cutaneous milieu. In this review, we summarize the current research topics on the CCL20/CCR6 axis and the therapeutic intervention of this axis for psoriasis.

Furue K ，Ito T ，Tsuji G ，Nakahara T ，Furue M ... -  《-》

Statins inhibit chemotactic interaction between CCL20 and CCR6 in vitro: possible relevance to psoriasis treatment.

Psoriasis is a chronic IL-23/Th17 pathway-associated skin disease. An increased expression of lesional CCL20 can recruit CCR6+ Th17, and lesional cytokine milieu persistently activates keratinocytes to produce CCL20. Lipid-lowering drugs, statins, are known to possess immune-modulating functions. In this study, we explored an inhibitory effect of statins on CCL20/CCR6 interaction. We demonstrated that IL-1β, TNF-α, and IL-17A significantly increased CCL20 production from HaCaT cells. However, these increments were markedly inhibited by fluvastatin and simvastatin, but not by pravastatin. In the chemotaxis migration assay, pretreatment with fluvastatin and simvastatin inhibited the migration of human CD4+ T cells towards CCL20. However, the level of CCR6 surface expression in memory CD4+ T cells was not affected. Our results suggest that not all, but specific types of statins may be of benefit in alleviating psoriasis partially via interrupting CCL20/CCR6 chemotactic interaction, the mechanism which may eventually lessen the infiltration of Th17 cells.

Kim TG ，Byamba D ，Wu WH ，Lee MG ... -  《-》

Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in an IL-23-dependent murine model.

Getschman AE ，Imai Y ，Larsen O ，Peterson FC ，Wu X ，Rosenkilde MM ，Hwang ST ，Volkman BF ... -  《-》

Development of psoriasis by continuous neutrophil infiltration into the epidermis.

Remarkable effects of anti-IL-17A and anti-IL-23 antibodies on psoriasis indicate deep involvement of IL-23/Th17 axis in the pathogenesis of psoriasis. According to the current immune theory, activation of dendritic cells initiates the generation of this axis. However, this theory is not enough to explain the mechanism, because the process of this activation is obscure and the antigen that is recognized by antigen-presenting cells and pathogenic T cells has long been unidentified. Therefore, I thought of another theory as follows. Neutrophils are attracted by LTB4 at subcorneal portion and infiltrate into the epidermis. At the time of neutrophil migration through the basement membrane, basal keratinocytes in G0/G1 phase enter the cell cycle and begin to proliferate, according to the principle, "detachment-mediated cell proliferation." This passing is continuously repeated and leads to elongation of rete ridges. The IL-23/Th17 axis is generated by interactions between infiltrated neutrophils and keratinocytes. Briefly, neutrophils infiltrated into the epidermis secrete IL-17A, which acts on keratinocytes to express CCL20, a ligand for the chemokine receptor CCR6. Keratinocytes perturbed by neutrophil infiltration produce HSP70, followed by production of IL-23 via TLR4 using HSP70 as an endogenous ligand for TLR4. Natural Th17 cells expressing CCR6 are recruited to psoriatic epidermis and expand there in the presence of IL-23 and IL-1β. In this manner, the framework of the IL-23/Th17 axis is created, which acts to maintain or exacerbate psoriasis. Noteworthy is the fact that this axis causes positive feedback loop, starting from IL-17A production by neutrophils and ending in IL-17A production by nTh17 cells. Therapeutic mechanisms of anti-IL-17A and anti-IL-23 antibodies, targeting neutrophils, were also described.

Katayama H 《-》

Anti-psoriasis effect of 18β-glycyrrhetinic acid by breaking CCL20/CCR6 axis through its vital active group targeting GUSB/ATF2 signaling.

Psoriasis is an immune-mediated chronic inflammatory skin disease. Current research suggests that the long-term persistence and recurrence of psoriasis are closely related to the feedback loop formed between keratinocytes and immune cells, especially in Th 17 or DC cells expressing CCR6. CCL20 is the ligand of CCR6. Therefore, drugs that block the expression of CCL20 or CCR6 may have a certain therapeutic effect on psoriasis. Glycyrrhetinic acid (GA) is the main active ingredient of the plant drug licorice and is often used to treat autoimmune diseases, including psoriasis. However, its mechanism of action is still unclear. Psoriasis like skin lesion model was established by continuously applying imiquimod on the back skin of normal mice and CCR6-/- mice for 7 days. The therapeutic and preventive effects of glycyrrhetinic acid (GA) on the model were observed and compared. The severity of skin injury is estimated through clinical PASI scores and histopathological examination. qRT-PCR and multiple cytoline assay were explored to detect the expression levels of cytokines in animal dorsal skin lesions and keratinocyte line HaCaT cells, respectively. The dermis and epidermis of the mouse back were separated for the detection of CCL20 expression. Transcription factor assay was applied to screen, and luciferase activity assay to validate transcription factors regulated by GA. Technology of surface plasmon laser resonance with LC-MS (SPR-MS), molecular docking, and enzyme activity assay were used to identified the target proteins for GA. Finally, we synthesized different derivatives of 18beta-GA and compared their effects, as well as glycyrrhetinic acid (GL), on the skin lesion of imiquimod-induced mice to evaluate the active groups of 18beta-GA. 18β-glycyrrhetinic acid (GA) improved IMQ-induced psoriatic lesions, and could specifically reduce the chemokine CCL20 level of the epidermis in lesion area, especially in therapeutic administration manner. The process was mainly regulated by transcription factor ATF2 in the keratinocytes. In addition, GUSB was identified as the primary target of 18βGA. Our findings indicated that the subject on molecular target research of glycyrrhizin should be glycyrrhetinic acid (GA) instead of glycyrrhizic acid (GL), because GL showed little activity in vitro or in vivo. Apart from that, α, β, -unsaturated carbonyl in C11/12 positions was crucial or unchangeable to its activity of 18βGA, while proper modification of C3 or C30 position of 18βGA may vastly increase its activity. Our research indicates that 18βGA exerted its anti-psoriasis effect mainly by suppressing ATF2 and downstream molecule CCL20 predominately through α, β, -unsaturated carbonyl at C11/12 position binding to GUSB in the keratinocytes, and then broke the feedback loop between keratinocytes and CCR6-expressing immune cells. GA has more advantages than GL in the external treatment of psoriasis. A highlight of this study is to investigate the influence of special active groups on the pharmacological action of a natural product, inspired by the molecular docking result.

Wei J ，Zhang J ，Hu F ，Zhang W ，Wu Y ，Liu B ，Lu Y ，Li L ，Han L ，Lu C ... -  《-》