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: 6.37). 04/2009; 129(9):2175-83. DOI: 10.1038/jid.2009.65
Source: PubMed

ABSTRACT 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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Available from: Andrew Blauvelt, Aug 18, 2015
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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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    • "CCL20 (also known as liver-and activation-regulated chemokine, LARC, or macrophage inflammatory protein- 3α, MIP-3α) is a CC-type chemokine, which activates chemokine receptor CCR6 and therefore plays an important role in homing CCR6 + lymphocytes and dendritic cells into secondary lymphoid organs and to sites of inflammation [20]. Memory T lymphocytes, na¨ıve and memory B cells, Langerhans cells, and subsets of immature dendritic cells all express CCR6 [20] and migrate to sites of CCL20 expression, for example, in atherosclerosis [20], inflammatory bowel disease [21], arthritis [19], chronic obstructive pulmonary disease [22], psoriasis [23], and tumor tissues [24]. Accordingly , an important role for CCL20 has been postulated in atherosclerosis, skin, and mucosal immunity, in rheumatoid arthritis, and in cancer [20]. "
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