Crosstalk between Keratinocytes and T Cells in a 3D Microenvironment: A Model to Study Inflammatory Skin Diseases

Abstract

The interaction between keratinocytes and immune cells plays a major role in the development of inflammatory skin diseases like psoriasis and atopic dermatitis. Pharmacological intervention to inhibit T cell-derived proinflammatory mediators is an effective therapy in the treatment of psoriasis. Here, we present a model to study the interaction between keratinocytes and T cells in a three-dimensional (3D) microenvironment, based on human skin equivalents populated with CD4+ T cells. T cell migration into the dermis initiated keratinocyte activation within 2 days, with hallmarks of a psoriasiform inflammation after 4 days. Expression of epidermal psoriasis marker genes was upregulated, and proinflammatory cytokines and chemokines were highly expressed. Disturbed epidermal differentiation was shown by downregulated filaggrin expression and involucrin expression in the spinous layer. These effects were mediated via soluble factors produced by the T cells. The psoriasiform inflammation was also observed using T helper type 1 (Th1)- and Th17-polarized CD4+ T cells. We validated our model by treatment with anti-inflammatory drugs that reduced the expression of proinflammatory cytokines and chemokines and suppressed the psoriasiform inflammation. We propose that our T cell-driven inflammatory skin equivalent model has potential to study the pathogenesis of inflammatory skin diseases and may serve as a preclinical screening tool for anti-inflammatory drugs.

Evaluation of antimicrobial peptides and cytokine production in primary keratinocyte cell culture from healthy and atopic beagles

“…IL-8 and KC-like) by atopic keratinocytes that may perpetuate a proinflammatory state in the atopic skin. These data are in agreement with previous studies showing an active involvement of AMPs and keratinocytes in the pathogenesis and/or exacerbation of AD (1,2,(26)(27)(28)(29)(30)(31)(32)(33). In particular, keratinocyte-secreted AMPs serve as alarmins able to orchestrate the cutaneous immune response in AD (27,29).…”

The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis

“…Indeed, the CD4 þ T cells, like the CD8 þ T cells, show oligoclonal expansion in psoriatic skin 49,50 . Activated CD4 þ T cells have been shown to induce a psoriasiform inflammation in epidermal cells in a recently set up 3D model of inflammatory skin disease 51 . In the past, it has been shown that injection of pre-psoriatic skin with CD4 þ , and not CD8 þ T cells, induced psoriasis 52 .…”

Reactive Oxygen Species in Psoriasis and Psoriasis Arthritis: Relevance to Human Disease

“…2) and possible cross-talk events between keratinocytes and immune cells. Recent investigation of the interactions between keratinocytes and T cells in a three-dimensional microenvironment showed CD4+ T cell migration into the dermis, which initiated keratinocyte activation within 2 days [67]. The psoriasiform inflammation was also observed using Th1-polarized and Th17-polarized CD4+ T cells.…”

“…The psoriasiform inflammation was also observed using Th1-polarized and Th17-polarized CD4+ T cells. Treatment with anti-inflammatory drugs reduced the expression of proinflammatory cytokines and chemokines, leading to the suppression of the psoriasiform inflammation [67]. In vitro keratinocyte coculture also allowed for the characterizing of the cross-talk of cytokines and growth factors, where periostin tuned the magnitude of keratinocyte proliferation and differentiation by interacting with the paracrine IL-1α/IL-6 loop [68].…”