Figure 2.

Model of skin immune response in dermatophytosis. Dermatophyte fungi invade the stratum corneum and release proteases (P) that degrade keratin for fungal growth and facilitate tissue invasion. Extracellular vesicles (EV) loaded with fungal virulence factors might be also released during infection. Host recognition of dermatophytes is mainly through CLR and TLR on myeloid cells and keratinocytes. The adapter protein CARD9 is a key molecule in fungal sensing that signals downstream various CLR and mediates cross-signaling of other innate receptors (TLR and NLR). Keratinocytes (KC) sense fungal hyphae and consequently release: 1) antimicrobial peptides (AMP; including cathelicidin and β-defensin) that are effector molecules promoting fungal clearance, 2) proinflammatory mediators (IL-6, CXCL8, TNF) that further stimulate inflammation and neutrophil recruitment or 3) immunosuppressive proteins, such as TSG-6, particularly in human infections with anthropophilic dermatophytes. Also, IL-6, IL-17, and IL-22 further stimulate KC activation. Neutrophils recognize fungi and trigger the intracellular activation of MAPK and NFκB pathways leading to proinflammatory cytokines/chemokines release that also enhance KC activation, recruit more inflammatory leukocytes and, probably, promote IL-17 producing-lymphocytes through IL-23 release. Neutrophils also secrete reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) that kill dermatophytes. The role of macrophages has not been directly evaluated during skin infections but these cells might also kill dermatophytes by IFN-γ-induced ROS and nitric oxide (NO) production or even resolve inflammation through phagocytosis of apoptotic neutrophils with production of anti-inflammatory cytokines (e.g.: IL-10). As for adaptive immunity, Langerhans cells (LC) are located in the epidermis and sense dermatophytes, migrate to skin draining lymph nodes and promote Th17 differentiation (ref. 51). Whereas in the dermis, different subsets of dendritic cells (DC) are probably involved in sensing fungal molecules and producing cytokines that drive IL-17- or IFN-γ- mediated immunity. IL-17A produced by adaptive Th17 cells and innate lymphocytes (γδT or ILC) boosts KC activation/proliferation and inhibits superficial fungal growth. Upon binding to IL-17RA/IL-17RC in KC, IL-17A activates Act1-TRAF6-NFkB/MAPK or STAT-3 intracellular pathways and induce cytokines/chemokines and AMP production. Furthermore, the IL-17/IL-17RA pathway transactivates epidermal growth factor receptor (EGFR) which promotes KC proliferation. During mild superficial experimental infection with M. canis, type 17 immunity restricts both fungal growth and an exacerbated type 1 (IFN-γ mediated) inflammation (ref. 51). Conversely, IFN-γ mediated-response suppresses cytokines related to the IL-17 pathway leading to an increased fungal burden. During T. benhamiae experimental infection both Th1 and Th17 phenotypes are induced and control the cutaneous mycoses (ref. 120). Dotted lines and question marks refer to mechanisms not directly demonstrated in the context of skin dermatophytosis. CARD9 signaling might be involved in various skin cells populations of the antifungal defense. KC, keratinocyte; LC, Langerhans cell; DC, dendritic cell; Ne, neutrophil; ILC, innate lymphoid cell; Mø, macrophages; sdLN, skin draining lymph node; CLR, C-type lectin receptor; TLR, Toll-like receptor; NLR, nucleotide-binding oligomerization domain (NOD)-like receptor; IL-17RA/IL-17RC, interleukin 17 receptor A/C; TCR, T cell receptor; MHC, major histocompatibility complex; AMP, antimicrobial peptides; ROS, reactive oxygen species; NO, nitric oxide; NETs, neutrophil extracellular traps; P, proteases; EV, extracellular vesicles.