Toll-like receptor 2 (TLR2) mediates intracellular signalling in human keratinocytes in response to Malassezia furfur

Abstract

Toll-like receptors (TLRs) are crucial players in the innate immune response to microbial invaders. The lipophilic yeast Malassezia furfur has been implicated in the triggering of scalp lesions in psoriasis. The aim of the present study was to assess the role of TLRs in the defence against M. furfur infection. The expression of the myeloid differentiation factor 88 (MyD88) gene, which is involved in the signalling pathway of many TLRs, was also analysed. In addition, a possible correlation of antimicrobial peptides of the beta-defensin family to TLRs was tested. Human keratinocytes infected with M. furfur and a variety of M. furfur-positive psoriatic skin biopsies were analysed by RT-PCR, for TLRs, MyD88, human beta-defensin 2 (HBD-2), HBD-3 and interleukin-8 (IL-8) mRNA expression. When keratinocytes were infected with M. furfur, an up-regulation for TLR2, MyD88, HBD-2, HBD-3 and IL-8 mRNA was demonstrated, compared to the untreated cells. The same results were obtained when psoriatic skin biopsies were analysed. The M. furfur-induced increase in HBD-2 and IL-8 gene expression is inhibited by anti-TLR2 neutralising antibodies, suggesting that TLR2 is involved in the M. furfur-induced expression of these molecules. These findings suggest the importance of TLRs in skin protection against fungi and the importance of keratinocytes as a component of innate immunity.

TLR2/MyD88-Dependent and -Independent Activation of Mast Cell IgE Responses by the Skin Commensal Yeast Malassezia sympodialis

“…Furthermore, the higher concentrations of M. sympodialis extract caused inhibition of phosphorylated-ERK1/2 in IgE receptor cross-linked mast cells, indicating that the modulation of the IL-6 release might be mediated through the ERK1/2 pathway. Our findings that M. sympodialis can activate mast cells via the TLR2/MyD88 pathway corroborate with the work of Baroni et al (36) who showed that human keratinocytes increase their gene expression of TLR2 and MyD88 following activation with Malassezia furfur. In another study, suppressed degranulation was determined upon combined stimulation of BMMCs with increasing concentrations of the TLR2 ligand Pam3CSK4 and IgE receptor cross-linking (37).…”

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

“…Recently, the adaptor protein MyD88 and its downstream pathway were shown to play a critical role in both spontaneous and carcinogeninduced tumor development [42,43]. Also, in rheumatoid arthritis and psoriasis, several works support evidence of an important role of endogenous TLR ligands that are involved in the induction of inflammation and initiation of diseases [44][45][46]. cPKC inhibitors that inhibit MyD88-dependent inflammatory signals downstream of TLR and IL-1R can be very promising molecules in the treatment of autoimmune inflammatory diseases, as it has been demonstrated with the AEB071 PKC inhibitor on psoriasis [47].…”

Psoriasis and Malassezia Yeasts

“…More recent studies have indicated that Malassezia yeasts cause exacerbation of psoriasis by triggering the release of cytokines, in particular IL-8 through a Toll-like receptor 2-mediated pathway (Baroni et al, 2006). However, convincing evidence of their importance in the pathogenesis of the disease is still lacking.…”