Human Keratinocytes' Response to Injury Upregulates CCL20 and Other Genes Linking Innate and Adaptive Immunity

Abstract

In the early stages of wound healing, keratinocytes become “activated” and release inflammatory molecules such as interleukin-1 and interleukin-8 that are linked to innate immune responses and neutrophil recruitment. It is unclear, however, whether keratinocytes release molecules linked to adaptive immune responses, e.g. CCL20, in their early state of activation without signals from infiltrating T cells. This study aims to isolate the immediate alterations in protective and inflammatory gene expression that occur in epidermal keratinocytes, with a particular focus on molecules associated with cell-mediated immunity. We used dispase-separated epidermis, followed by intercellular disassociation by trypsinization, as a model for epidermal injury. We obtained a pure population of keratinocytes using flow cytometry. As a control for uninjured epidermis, we performed laser capture microdissection on normal human skin. Sorted keratinocytes had an early burst of upregulated gene expression, which included CCL20, IL-15, IL-23A, IFN-κ, and several antimicrobial peptides. Our results provide insight into the potential role of keratinocytes as contributors to cell-mediated inflammation, and expand knowledge about gene modulation that occurs during early wound healing. Our findings may be relevant to cutaneous diseases such as psoriasis, where micro-injury can trigger the formation of psoriatic plaques at the site of trauma.

Psoriasis: Keratinocytes or Immune Cells – Which Is the Trigger?

“…IL-23 is also involved in the induction of JAK2 and TYK2, resulting in the preferential upregulation of STAT3 [33]. Sources of IL-23 include monocytes (also under the influence of CCL20 [29]) in the dermis, and keratinocytes and Langerhans cells in the epidermis. Binding of IL-23 to the IL-23 receptor expressed by Th17 cells triggers intracellular downstream signaling that results in the production of IL-17A (the most potent IL-17 activator [35]) and IL-17F [36] (less potent than IL-17A, despite being 50% homologous [35]).…”

“…These factors can stimulate keratinocytes to release CCL20, leading to PDC-independent MDC activation and T-helper 17 (Th17) cell recruitment [29]. Once activated, MDCs orchestrate the inflammatory phases of psoriasis.…”

Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome

“…In Tg KLK5 skin, we found elevated expression of Il 1, Il 18, and Il 23, which could explain the presence of Th17 cells. The treatment of healthy keratinocytes with TNF in duces the expression of CCL20, a molecule involved in Th17 recruitment (Kennedy Crispin et al, 2012). It is thus possible that enhanced Tnf  and Il 1 production in Tg KLK5 con tributes to Ccl20 expression leading to Th17 recruitment.…”

The Immunopathogenesis of Psoriasis

“…1). 1,8,9 Skin infection may also activate immune pathways leading to production of TNF or IFN-a in the skin. 1 TNF induces CCL20 and mediates recruitment of neutrophils by stimulating keratinocyte-derived CXCL chemokines, such as CXCL8.…”