Synergistic induction of IL-23 by TNFα, IL-17A, and EGF in keratinocytes
Introduction
IL-23 is a heterodimeric cytokine composed of a unique p19 subunit and a p40 subunit that is shared with IL-12 [1]. It is an inflammatory cytokine essential for maintaining Th17 cell activity by enhancing Th17 cell proliferation, survival, and Th17 cytokine production [2]. IL-23 plays many critical roles in psoriasis pathogenesis, as demonstrated by its overexpression in psoriatic skin [3], the induction of psoriasis-like phenotypes in mice by intradermal IL-23 injection [4], the association of genetic variants in genes of IL-23 signaling with susceptibility or resistance to psoriasis [5], [6], and the alleviation of psoriatic conditions by anti–IL-23 antibodies in mouse models [7]. More importantly, antibodies against either IL23p40 or IL23p19 have demonstrated clinical efficacy in human psoriasis therapy [8], [9].
Despite the importance of IL-23 in psoriasis pathogenesis, the regulation of IL-23 expression in psoriasis remains largely elusive. IL-23 is primarily expressed in macrophages and dendritic cells in response to bacterial and viral infections and pathogen-associated molecular patterns [10], [11], [12], and dendritic cells are generally considered to be the primary source of IL-23 in psoriasis [3]. Despite high levels of IL-23 found in the epidermis of psoriatic skin [13], [14], [15], [16], [17], IL-23 expression in keratinoctyes remains a controversial issue. The expression of IL-23 mRNA has been detected in keratinocytes under different conditions [14], [18], [19]. However, only low levels of IL-23 protein were detected in keratinocytes under culture conditions that are not relevant to psoriasis [19]. To date, whether or not IL-23 protein is produced from keratinocytes remains a debatable issue. In this study, we aimed to determine whether IL-23 cytokine is expressed in keratinocytes and to identify the signals that trigger IL-23 expression in keratinocytes in an attempt to define the role of keratinocyte IL-23 expression in psoriasis pathogenesis.
Section snippets
Primary keratinocyte culture and reagents
Skin biopsy specimens (6 mm) were obtained from both the lesional skin of patients with psoriasis and the skin of individuals without psoriasis under an Oregon Health & Science University Institutional Review Board-approved protocol. The epidermis was trimmed off and minced into 1x1 mm2 skin islets. The skin islets were planted on collagen-coated plates as described [20]. Keratinocytes from the outgrowth were trypsinized and plated in 12-well plates for the assay. The keratinocyte cultures were
IL-23 is induced by TNFα and IL-17A in human keratinocytes
To investigate the possibility of keratinocytes acting as a source of IL-23 production in psoriasis, we first analyzed the production of IL-23 by primary human keratinocytes in response to potential psoriatic cytokines including TNFα, IL-17A, IL-22, IL-17F, and interferonγ (IFN-γ). We found that maximal IL23p19 mRNA was induced by combined treatment with TNFα and IL-17A (Fig. 1A). Marginal IL23p19 expression was induced by either TNFα or IL-17A alone. IL23p19 expression was moderately induced
CRediT authorship contribution statement
Benjamin Ehst: Conceptualization, Resources, Writing - review & editing. Zhiping Wang: Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization. Justin Leitenberger: Resources. Danielle McClanahan: Resources. Rachel De La Torre: Data curation, Investigation. Erika Sawka: Resources. Alex G. Ortega-Loayza: Resources. Jennifer Strunck: Resources. Teri Greiling: Resources, Writing - review & editing. Eric Simpson: Resources, Writing - review & editing. Yuangang Liu:
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We thank Melanie Swinson for procuring clinical samples and Clara Stemwedel for editing the manuscript. This study was partially supported by NIAMS R03 AR066736, and R01 AR070645.
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2022, Journal of Investigative DermatologyCitation Excerpt :Variants of genes, including TYK2, TRAF3IP2, IL23A, and IL23R, then mediate differentiation of the autoimmune response into a Tc17 type that increases KC proliferation and causes recruitment of neutrophilic granulocytes through the production of IL-17, IL-22, TNF-α, and other cytokines (Ortega et al., 2009). The surrounding cytokine milieu with a strong production of IL-23 by dermal DCs, monocytes (Lee et al., 2004), and KCs (Ehst et al., 2021; Piskin et al., 2006) maintains the activation of Tc17 cells, which, through the production of IFN-γ, increase the expression of ERAP1 (Saric et al., 2002) and HLA-C∗06:02 (Gobin et al., 1999) and thus promote autoantigen presentation. This may lead to a self-perpetuating mechanism of antigen presentation, T-cell stimulation, and Tc17 differentiation in the context of the psoriatic autoimmune response (Figure 1e).
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Current address: Oregon Medical Research Center, Portland, OR 97223, USA.