Sporothrix globosa melanin regulates autophagy via the TLR2 signaling pathway in THP-1 macrophages

Abstract

Melanin, an important virulence factor of pathogenic fungi, has been shown to suppress host immune responses in multiple ways. Autophagy is a vital cellular mechanism underlying the host’s innate immunity against microbial infections. However, the potential influence of melanin on autophagy has not been explored. We investigated the effect of melanin on autophagy in macrophages, which play a key role in controlling Sporothrix spp. infection, as well as the mechanism of melanin interaction with Toll-like receptor (TLR)-induced pathways. Sporothrix globosa conidia (wild-type and melanin-deficient mutant strains) or yeast cells were co-cultured with THP-1 macrophages to demonstrate that, although S. globosa infection led to the activation of autophagy-related proteins and increased autophagic flux, S. globosa melanin suppressed macrophage autophagy. Incubation with S. globosa conidia also increased the expression levels of reactive oxygen species and multiple proinflammatory cytokines (interleukin-6, tumor necrosis factor-α, interleukin-1β and interferon-γ) in macrophages. These effects were attenuated as melanin presented. Furthermore, while S. globosa conidia significantly increased the expression of both TLR2 and TLR4 in macrophages, the knockdown of TLR2, but not TLR4, with small interfering RNA suppressed autophagy. Overall, this study revealed the novel immune defense ability of S. globosa melanin to inhibit macrophage functionality by resisting macrophage autophagy through the regulation of TLR2 expression.

Role of Dectin-1 in immune response of macrophages induced by Fonsecaea monophora wild strain and melanin-deficient mutant strain

“…Melanin is also involved in regulating the expression of TLR2 and TLR4 receptors, impairing the killing efficiency of S. globosa (Guan et al 2021 ). Moreover, S. globosa melanin inhibits macrophage autophagy by regulating TLR2 expression and thus suppresses the immune defence of macrophages (Guan et al 2023 ). Recognition of F. monophora (including FcγR, CR, Dectin-2, Mincle, MelLec, TLR, etc.)…”

Extracellular vesicles derived from Talaromyces marneffei contain immunogenic compounds and modulate THP-1 macrophage responses

“…For example, β-glucans present in the fungal cell wall can activate the dectin-1 receptor on THP-1 cells, leading to the production of pro-inflammatory cytokines and pro-inflammatory mediators ( 54 ). Moreover, it may be possible that the melanin or melanoprotein inside the EVs can activate THP-1 macrophages by modulating toll-like receptor (TLR) 2 or TLR 4 on the THP-1 surfaces ( 55 , 56 ). Second, delivery of bioactive compounds; T. marneffei EVs contain various bioactive compounds such as alkaline serine protease (B8M8A7_TALSN) or extracellular metalloprotease (A0A093UPI6_TALMA), which can directly damage host cells or modulate host immune responses.…”