Malassezia‐derived aryl hydrocarbon receptor ligands enhance the CCL20/Th17/soluble CD163 pathogenic axis in extra‐mammary Paget's disease

Abstract

Malassezia yeast play a role in the pathogenesis of chronic dermatitis, especially in apocrine areas, by polarizing the local immunologic background to a Th2/Th17 state through aryl hydrocarbon receptor (AhR)-dependent pathways. Extra-mammary Paget's disease (EMPD) is an adenocarcinoma of apocrine origin, and except for cases associated with Malassezia yeast and their metabolites, the lesions typically develop in areas not exposed to environmental material. The purpose of this study was to investigate (a) the immunomodulatory effects of Malassezia metabolites on normal human keratinocytes (NHKCs), focusing on interleukin (IL)-17 and related cytokines/ chemokines (IL-23, IL-36γ, CCL20), (b) the expression of these factors in lesion-affected skin in EMPD and (c) the activation of tumor-associated macrophages (TAMs) by these factors. Malassezia metabolites augmented the expression of cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), CCL20 and IL-36γ mRNA in NHKCs in vitro. In lesion-affected skin of patients with EMPD, epidermal keratinocytes expressed CYP1A1 and CCL20. In addition, Paget cells expressed CCL20 and IL-23. IL-17-producing cells were distributed adjacent to Paget cells. Compared to healthy donors, patients with EMPD exhibited significantly increased serum levels of soluble (s)CD163, CXCL5, CXCL10 and CCL20. In addition, serum levels of sCD163 decreased significantly following tumor resection. Our study demonstrates a possible mechanism for the development of EMPD involving AhR-mediated signalling by epidermal keratinocytes and RANKL-induced recruitment of Th17 cells and TAMs. K E Y W O R D Saryl hydrocarbon receptor, extra-mammary Paget's disease, Malassezia, proinflammatory cytokines, tumor-associated M2 macrophages

IL-23 Expression in Stewart-Treves Syndrome: Two Case Reports and Immunohistochemical Investigation

“…For example, several reports suggested the significance of IL-17 signaling in keratinocytes in the tumor formation of cutaneous squamous cell carcinoma [10][11][12]. More recently, we have also reported on the possible correlation between the CCL20/IL-23/IL-17 axis in the development of extramammary Paget's cells [7]. Notably, IL-17 is not only a signal for cell proliferation, but it also activates MMP2 and MMP9 to induce angiogenesis in several cancer types [13,14].…”

“…Since tumor-associated macrophages and tumor-associated neutrophils are significant components of the microenvironment of solid tumors in the majority of cancers [8,9], IL-23 could be one of the crucial factors for the progression of cancers, including skin cancers. Indeed, as we have previously reported, Paget's cells as well as dermal myeloid cells produce IL-23, leading to the induction of IL-17 in the lesional skin in extramammary Paget's cells [7]. In addition to inducing IL-17 expression, IL-23 inhibits apoptosis; thus, promoting tumor progression [6].…”

“…IL-23 plays an important role in inducing Th17 cell proliferation as well as in the angiogenesis of tumors [3][4][5][6][7]. Indeed, Nie et al [4] reported that IL-23 promotes the recruitment of M2 macrophages and neutrophils, which secrete immunosuppressive cytokines and vascular endothelial growth factor as well as matrix metalloproteinase 9 (MMP9) into tumor tissues.…”

“…IL-17-producing cells are widely detected and could play a significant role in skin cancers [7,[10][11][12]. For example, several reports suggested the significance of IL-17 signaling in keratinocytes in the tumor formation of cutaneous squamous cell carcinoma [10][11][12].…”

Significance of Immunosuppressive Cells as a Target for Immunotherapies in Melanoma and Non-Melanoma Skin Cancers

“…Among the inducers of TANs, IL-17 could play a significant role in developing skin cancers. Indeed, several reports have suggested the significance of IL-17 in the development of skin cancers such as cutaneous squamous cell carcinoma (cSCC) [61,62] and extramammary Paget's disease (EMPD) [23]. For example, Wu et al reported that IL-17 signaling in keratinocytes drives IL-17-dependent sustained activation of the TRAF4-ERK5 axis, leading to keratinocyte proliferation and tumor formation in cSCC [61].…”