Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4-mediated suppression of IL-10.
BACKGROUND
Atopic dermatitis (AD) is a T cell-mediated inflammatory skin disease, with TH2 cells initiating acute flares. This inflamed skin is immediately colonized with Staphylococcus aureus, which provides potent Toll-like receptor (TLR) 2 ligands. However, the effect of TLR2 ligands on the development of TH2-mediated AD inflammation remains unclear.


OBJECTIVE
We investigated the progression of TH2 cell-mediated dermatitis after TLR2 activation.


METHODS
Using models for acute AD with TH2 cells initiating cutaneous inflammation, we investigated the consequences of TLR2 activation. Dermatitis, as assessed by changes in ear skin thickness and histology, was analyzed in different BALB/c and C57BL/6 wild-type and knockout mouse strains, and immune profiling was carried out by using in vitro and ex vivo cytokine analyses.


RESULTS
We show that TH2 cell-mediated dermatitis is self-limiting and depends on IL-4. Activation of TLR2 converted the limited TH2 dermatitis to chronic cutaneous inflammation. We demonstrate that the concerted activation of TLR2 and IL-4 receptor on dendritic cells is sufficient for this conversion. As an underlying mechanism, we found that the combinatorial sensing of the innate TLR2 ligands and the adaptive TH2 cytokine IL-4 suppressed anti-inflammatory IL-10 and consequently led to the exacerbation and persistence of dermatitis.


CONCLUSIONS
Our data demonstrate that innate TLR2 signals convert transient TH2 cell-mediated dermatitis into persistent inflammation, as seen in chronic human AD, through IL-4-mediated suppression of IL-10. For the first time, these data show how initial AD lesions convert to chronic inflammation and provide another rationale for targeting IL-4 in patients with AD, a therapeutic approach that is currently under development.
Department of Dermatology, Eberhard Karls University, Tübingen, Germany.
Susanne
S
Kaesler
Department of Dermatology, Eberhard Karls University, Tübingen, Germany.
Thomas
T
Volz
Department of Dermatology, Eberhard Karls University, Tübingen, Germany.
Yuliya
Y
Skabytska
Department of Dermatology, Eberhard Karls University, Tübingen, Germany.
Martin
M
Köberle
Department of Dermatology, Eberhard Karls University, Tübingen, Germany.
Ulrike
U
Hein
Department of Dermatology, Eberhard Karls University, Tübingen, Germany.
Ko-Ming
KM
Chen
Department of Dermatology, Eberhard Karls University, Tübingen, Germany; Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Emmanuella
E
Guenova
Department of Dermatology, Eberhard Karls University, Tübingen, Germany.
Florian
F
Wölbing
Department of Dermatology, Eberhard Karls University, Tübingen, Germany.
Martin
M
Röcken
Department of Dermatology, Eberhard Karls University, Tübingen, Germany; Department of Dermatology and Allergy Biederstein, Technische Universität München, Munich, Germany. Electronic address: tilo.biedermann@med.uni-tuebingen.de.
Tilo
T
Biedermann
D000818:Animals; D002908:Chronic Disease; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D003876:Dermatitis, Atopic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D012867:Skin / Q000276:immunology* / Q000473:pathology; D013207:Staphylococcal Skin Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013211:Staphylococcus aureus / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*
C556062:IL10 protein, mouse; D008024:Ligands; D019948:Receptors, Interleukin-4; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D016753:Interleukin-10; D015847:Interleukin-4
IL-10; IL-4; Staphylococcus aureus; T(H)2; Toll-like receptor 2; atopic dermatitis; innate immunity