Toll‐like receptor 4 attenuates a murine model of atopic dermatitis through inhibition of langerin‐positive DCs migration

Abstract

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that is often associated with skin barrier dysfunction leading to a higher frequency of bacterial and viral skin infections. Toll-like receptor (TLR) 4 on resident skin cells was involved in sensing pathogens and eliciting pathogen-specific innate and adaptive immune responses. Previous studies have demonstrated that TLR4 was linked to AD severity in context of pathogen infection. However, the immune regulatory role of TLR4 in AD remains to be defined. We here investigated the immune regulatory function of TLR4 in AD induced by repeated epicutaneous application of a hapten, 2,4-dinitrochlorobenzene (DNCB). Our results showed that TLR4-deficient (TLR4 ) mice exhibited more severe AD symptoms than WT mice after DNCB challenge. The DNCB-treated TLR4 mice also displayed higher expression levels of inflammatory cytokines and stronger Th2 response than WT counterparts. Moreover, the skin expression of thymic stromal lymphopoietin (TSLP), an important potential contributor to allergic inflammation, was significantly elevated in TLR4 mice compared with that in WT mice upon DNCB administration. Furthermore, we demonstrated that the migration of langerin-positive dendritic cells (DCs) into draining lymph nodes was enhanced in TLR4 mice following DNCB challenge, which is partially dependent on the production of pro-inflammatory cytokine TNF-α. Together, these results determined that TLR4 affected the hapten-induced skin inflammation in the absence of exogenous pathogen infection, suggesting that TLR4 not only regulates infection but also may serve as a modulator of the immune response during AD development.

Gut Microbiota, Probiotics, and Their Interactions in Prevention and Treatment of Atopic Dermatitis: A Review

“…Furthermore, the single nucleotide polymorphisms (SNPs) related to oxidative stress and inflammation indicating that there was a close association between TLR2, TLR4, and TNF and traffic-related air pollution, and this revealed the geneenvironment interactions in the development of AD (85). In TLR4 -/mice, hapten (2,4-dinitrochlorobenzene)-induced AD symptoms and Th2-type inflammatory responses were more severe than wild-type mice and increased the migration of DCs into draining lymph nodes (86). This indicated that TLR4 mediated immune responses associated with AD development.…”

Pathogenic Mechanism of Der p 38 as a Novel Allergen Homologous to RipA and RipB Proteins in Atopic Dermatitis

“…In contrast to our results, the upregulation of TLR4 expression may be related to modulation of AD development as well as protection of infection. Deficiency of TLR4 induces the aggravation of AD after 2,4-dinitrochlorobenzene (DNCB) administration, via increased Th2 responses (22). In addition, TLR4 suppresses the pathogenic mechanism of AD induced by Aspergillus fumigatus extracts (20).…”

“…However, studies have reported that TLR4 is a negative regulator in the pathogenic mechanism of AD. Deletion of TLR4 suppresses AD-like symptoms and skin inflammation in AD-like mice due to fungus allergens and 2,4-dinitrochlorobenzene (DNCB) (20)(21)(22). Der p 2 does not induce AD via TLR4, but through TLR2 (23).…”

Schwann cells as underestimated, major players in human skin physiology and pathology

“…The use of mouse lines to label and conditionally disrupt genes in SCs can then be adapted to the established mouse models of psoriasis and AD. [ ] Given the findings that global p75NTR KO alters the cutaneous inflammatory response, SC‐specific deletion of p75NTR (eg Plp‐CreER T2 p75NTR lox/lox ) should be done to validate the role of SC p75NTR signalling in these disease models. Finally, mouse lines that allow conditional disruption of SC activation are already existing (eg Plp‐CreER T2 Sox10 lox/lox ).…”