Human thioredoxin, a damage-associated molecular pattern and Malassezia-crossreactive autoallergen, modulates immune responses via the C-type lectin receptors Dectin-1 and Dectin-2

Abstract

Human thioredoxin (hTrx), which can be secreted from cells upon stress, functions in allergic skin inflammation as a T cell antigen due to homology and cross-reactivity with the fungal allergen Mala s13 of the skin-colonizing yeast Malassezia sympodialis . Recent studies have shown that cell wall polysaccharides of Malassezia are detected by the immune system via the C-type lectin receptors Dectin-1 and Dectin-2, which are expressed on myeloid cells. Therefore, this study aimed to investigate a putative interaction between Dectin-1, Dectin-2 and the allergens Mala s13 and hTrx. Stimulation of human monocyte-derived dendritic cells or macrophages with Mala s13 or hTrx resulted in remarkable secretion of IL-1β and IL-23. Blocking experiments suggest that hTrx induces IL-23 by Dectin-1 binding and IL-1β by binding to either Dectin-1 or Dectin-2. Regarding Mala s13, Dectin-1 appears to be involved in IL-1β signaling. Interference of Syk kinase function was performed to investigate downstream signaling, which led to diminished hTrx responses. In our experiments, we observed rapid internalization of Mala s13 and hTrx upon cell contact and we were able to confirm direct interaction with Dectin-1 as well as Dectin-2 applying a fusion protein screening platform. We hypothesize that this cytokine response may result in a Th2/Th17-polarizing milieu, which may play a key role during the allergic sensitization in the skin, where allergen presentation to T cells is accompanied by microbial colonization and skin inflammation.

Janus kinase inhibitors for the therapy of atopic dermatitis

“…Cerdulatinib, also known as DMVT-502, is a dual JAK and SYK inhibitor that has demonstrated efficacy in lymphoma as an oral therapy. Spleen tyrosine kinase (SYK) is involved in mediating proinflammatory signaling, including via the dectin-1 receptor, which is implicated in the inflammatory processes of AD [ 37 ]. Inhibition accordingly leads to a reduction in the release of proinflammatory cytokines such as IL-1.…”

The Role of IL-17-Producing Cells in Cutaneous Fungal Infections

“…Malassezia folliculitis is often observed in adolescents and is characterized by follicular erythematous papules localized on the chest, back, and upper arms. Malassezia species have β-glucan-enriched cell walls [79], and drives responses mediated by TLR2 [80], Dectin-1 [81], Dectin-2 [81], MINCLE [82], mannose receptor [83], and TLR9 [84].…”

Host responses in anex-vivohuman skin model challenged withMalassezia sympodialis

“…The M. sympodialis genome contains 13 allergen genes, Mala S1, Mala S5 to S13 and three orthologs of M. furfur allergens (Mala F2, 3, and 4) (Gioti et al, 2013;Andersson et al, 2003). Some of these allergens are highly similar to human proteins (Mala S11, Mala S13) and have been specifically linked to cross-reactive immune responses (Gioti et al, 2013;Schmid-Grendelmeier et al, 2005;Roesner et al, 2019).…”