Th17 Cytokines Stimulate CCL20 Expression in Keratinocytes In Vitro and In Vivo: Implications for Psoriasis Pathogenesis

Department of Dermatology, Oregon Health & Science University, Portland, Oregon 97239, USA.
Journal of Investigative Dermatology (Impact Factor: 7.22). 04/2009; 129(9):2175-83. DOI: 10.1038/jid.2009.65
Source: PubMed


T helper (Th) 17 cells have recently been implicated in psoriasis pathogenesis, but mechanisms of how these cells traffic into inflamed skin are unknown. By immunostaining for interleukin (IL)-17A and IL-22, we show numerous cells present in psoriasis lesions that produce these cytokines. We next found that Th17 cytokines (IL-17A, IL-22, and tumor necrosis factor (TNF)-alpha) markedly increased the expression of CC chemokine ligand (CCL) 20, a CC chemokine receptor (CCR)6 ligand, in human keratinocyte monolayer and raft cultures in a dose- and time-dependent manner. Lastly, we showed in mice that subcutaneous injection with recombinant IL-17A, IL-22, or TNF-alpha led to the upregulation of both CCL20 and CCR6 expression in skin as well as cutaneous T-cell infiltration. Taken together, these data show that Th17 cytokines stimulate CCL20 production in vitro and in vivo, and thus provide a potential explanation of how CCR6-positive Th17 cells maintain their continual presence in psoriasis through a positive chemotactic feedback loop.

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    • "Within 24 h of infection, expression of Il33, Tslp and Ccl20 transcripts were elevated in infected epidermis relative to naïve skin, indicating that the epidermis is a source of stimuli for APCs and T cells. For example, IL-33 and TSLP promote both the development of a wound healing phenotype in dermal APCs and Th2 polarisation in skin-draining lymph nodes (Cook et al., 2011; Gause et al., 2013), whilst CCL20 is a chemoattractant for CCR6 + T cells and immature DCs in murine models of psoriasis (Harper et al., 2009), and thus may be involved in driving these processes following exposure to cercariae. In addition, hair follicle keratinocytes specifically secrete chemokines required to recruit LC precursors to the epidermis within 24 h of LC depletion in mice (Nagao et al., 2012), providing further evidence that these cells promote leukocyte chemotaxis. "
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    ABSTRACT: Keratinocytes constitute the majority of cells in the skin’s epidermis, the first line of defence against percutaneous pathogens. Schistosome larvae (cercariae) actively penetrate the epidermis to establish infection, however the response of keratinocytes to invading cercariae has not been investigated. Here we address the hypothesis that cercariae activate epidermal keratinocytes to promote the development of a pro-inflammatory immune response in the skin. C57BL/6 mice were exposed to Schistosoma mansoni cercariae via each pinna and non-haematopoietic cells isolated from epidermal tissue were characterised for the presence of different keratinocyte sub-sets at 6, 24 and 96 h p.i. We identified an expansion of epidermal keratinocyte precursors (CD45−, CD326−, CD34+) within 24 h of infection relative to naïve animals. Following infection, cells within the precursor population displayed a more differentiated phenotype (α6integrin−) than in uninfected skin. Parallel immunohistochemical analysis of pinnae cryosections showed that this expansion corresponded to an increase in the intensity of CD34 staining, specifically in the basal bulge region of hair follicles of infected mice, and a higher frequency of keratinocyte precursor Ki67+ nuclei in both the hair follicle and interfollicular epidermis. Expression of pro-inflammatory cytokine and stress-associated Keratin 6b genes was also transiently upregulated in the epidermal tissue of infected mice. In vitro exposure of keratinocyte precursors isolated from neonatal mouse skin to excretory/secretory antigens released by penetrating cercariae elicited IL-1α and IL-1β production, supporting a role for keratinocyte precursors in initiating cutaneous inflammatory immune responses. Together, these observations indicate that S. mansoni cercariae and their excretory/secretory products act directly upon epidermal keratinocytes, which respond by initiating barrier repair and pro-inflammatory mechanisms similar to those observed in epidermal wound healing.
    International Journal for Parasitology 01/2015; 193(4). DOI:10.1016/j.ijpara.2014.11.002 · 3.87 Impact Factor
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    • "The C-C chemokine CCL20, also known as macrophage infiltrating factor protein-3 α (MIP-3 α) and liver activation regulated chemokine (LARC), however, is the only known ligand for the receptor CCR6, which in turn is the only known receptor for CCL20 [4]. CCR6-CCL20 interactions have been shown to be involved in several autoimmune and inflammatory processes such as rheumatoid arthritis, [5] multiple sclerosis [6], [7], psoriasis [8], and inflammatory bowel disease [9]. Of note, inflammation is particularly important in sporadic intestinal tumorigenesis [10]–[15]. "
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    ABSTRACT: Interactions between the inflammatory chemokine CCL20 and its receptor CCR6 have been associated with colorectal cancer growth and metastasis, however, a causal role for CCL20 signaling through CCR6 in promoting intestinal carcinogenesis has not been demonstrated in vivo. In this study, we aimed to determine the role of CCL20-CCR6 interactions in spontaneous intestinal tumorigenesis. CCR6-deficient mice were crossed with mice heterozygous for a mutation in the adenomatous polyposis coli (APC) gene (APCMIN/+ mice) to generate APCMIN/+ mice with CCR6 knocked out (CCR6KO-APCMIN/+ mice). CCR6KO-APCMIN/+ mice had diminished spontaneous intestinal tumorigenesis. CCR6KO-APCMIN/+ also had normal sized spleens as compared to the enlarged spleens found in APCMIN/+ mice. Decreased macrophage infiltration into intestinal adenomas and non-tumor epithelium was observed in CCR6KO-APCMIN/+ as compared to APCMIN/+ mice. CCL20 signaling through CCR6 caused increased production of CCL20 by colorectal cancer cell lines. Furthermore, CCL20 had a direct mitogenic effect on colorectal cancer cells. Thus, interactions between CCL20 and CCR6 promote intestinal carcinogenesis. Our results suggest that the intestinal tumorigenesis driven by CCL20-CCR6 interactions may be driven by macrophage recruitment into the intestine as well as proliferation of neoplastic epithelial cells. This interaction could be targeted for the treatment or prevention of malignancy.
    PLoS ONE 05/2014; 9(5):e97566. DOI:10.1371/journal.pone.0097566 · 3.23 Impact Factor
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    • "Both CCR6 and CXCR3 play an important role in the recruitment of CD4+ T cells in many autoimmune diseases. CCR6+ cells have been implicated in the pathogenesis of experimental autoimmune encephalitis, experimental autoimmune uveitis, psoriasis, asthma, and many other diseases [27]–[29]. Similarly, CXCR3+ cells are involved in rheumatoid arthritis, systemic lupus erythematosus [13]. Our central hypothesis was that Th1 and Th17 chemokine receptors are needed for the progression of dry eye disease. "
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    ABSTRACT: CD4(+) T cells are essential to pathogenesis of ocular surface disease in dry eye. Two subtypes of CD4(+) T cells, Th1 and Th17 cells, function concurrently in dry eye to mediate disease. This occurs in spite of the cross-regulation of IFN-γ and IL-17A, the prototypical cytokines Th1 and Th17 cells, respectively. Essential to an effective immune response are chemokines that direct and summon lymphocytes to specific tissues. T cell trafficking has been extensively studied in other models, but this is the first study to examine the role of chemokine receptors in ocular immune responses. Here, we demonstrate that the chemokine receptors, CCR6 and CXCR3, which are expressed on Th17 and Th1 cells, respectively, are required for the pathogenesis of dry eye disease, as CCR6KO and CXCR3KO mice do not develop disease under desiccating stress. CD4(+) T cells from CCR6KO and CXCR3KO mice exposed to desiccating stress (DS) do not migrate to the ocular surface, but remain in the superficial cervical lymph nodes. In agreement with this, CD4(+) T cells from CCR6 and CXCR3 deficient donors exposed to DS, when adoptively transferred to T cell deficient recipients manifest minimal signs of dry eye disease, including significantly less T cell infiltration, goblet cell loss, and expression of inflammatory cytokine and matrix metalloproteinase expression compared to wild-type donors. These findings highlight the important interaction of chemokine receptors on T cells and chemokine ligand expression on epithelial cells of the cornea and conjunctiva in dry eye pathogenesis and reveal potential new therapeutic targets for dry eye disease.
    PLoS ONE 11/2013; 8(11):e78508. DOI:10.1371/journal.pone.0078508 · 3.23 Impact Factor
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