Concurrent exposure to a dectin-1 agonist suppresses the Th2 response to epicutaneously introduced antigen in mice
Jing-Yi Lin
2
Jau-Shiuh Chen
0
Pei-Chun Chen
1
Ming-Hui Chung
0
Ching-Yi Liu
0
Shi-Chuen Miaw
3
Li-Fang Wang
0
0
Department of Dermatology, National Taiwan University Hospital
,
No.7, Chung-Shan South Road, Taipei
,
Taiwan
1
Department of Statistics and Informatics Science, Providence University
,
Taichung
,
Taiwan
2
Department of Dermatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine
,
Taoyuan
,
Taiwan
3
Graduate Institute of Immunology of National Taiwan University Hospital and National Taiwan University College of Medicine
,
Taipei
,
Taiwan
Background: Epicutaneous sensitization with protein allergen that induces predominant Th2 responses is an important sensitization route in atopic dermatitis. Fungal components have been shown to modulate Th cell differentiation. However, the effects of fungal components on epicutaneous sensitization are unclear. Results: In this study, we showed that co-administration of curdlan, a dectin-1 agonist, during epicutaneous ovalbumin sensitization of BALB/c mice decreased the IL-5 and IL-13 levels in supernatants of lymph node cell ovalbumin reactivation cultures. Mechanistically, curdlan co-administration decreased IL-4 and IL-1 expressions in draining lymph nodes. Curdlan co-administration also lower the migration of langerin+ CD103- epidermal Langerhans cells into draining lymph nodes at 96 hours post-sensitization which might be attributed to decreased expressions of IL-18 and IL-1 in patched skin. Moreover, adoptive transfer of CFSE-labeled transgenic CD4 T cells confirmed that curdlan co-administration decreased the proliferation and IL-4-production of ovalbumin -specific T cells primed by epidermal Langerhans cells. Conclusions: These results indicated that concurrent exposure to a dectin-1 agonist suppresses the epicutaneously induced Th2 response by modulating the cytokine expression profiles in draining LNs and the migration of epidermal Langerhans cells. These results highlight the effects of fungal components on epicutaneous allergen sensitization in atopic diseases.
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Background
The prevalence of atopic diseases has progressively
increased in recent decades. The interaction between
genetic susceptibility for atopy with varying
environmental allergen exposures plays a central role in the
pathogenesis of atopic diseases [1]. Allergens that provoke
atopic diseases are ubiquitously distributed
environmental protein antigens. Atopic dermatitis (AD) is often the
first manifestation of the atopic triad and typically marks
the onset of the atopic march [2].
The route of protein allergen sensitization in AD
remains unclear. However, compelling clinical evidence
suggests that epicutaneous exposure to protein antigen
is one of the important sensitization routes for AD [3,4].
In animal models, we and others have demonstrated that
epicutaneous sensitization with protein antigens induces
predominate Th2 and weak Th1 responses, which leads
to AD-like skin lesions and the development of asthma
[5,6]. Epicutaneous sensitization with protein antigen
also induces a modest Th17 response [7,8]. However,
cross-priming with an epicutaneously introduced protein
antigen generates Th1, but not Th2 cells [9]. An
epicutaneously induced Th2 response requires the production
of IL-10 and IL-13 [10,11]. Because defective IFN-
production during infancy may be an important cause for
sustained elevation of Th2 responses in atopic children,
determining how to suppress Th2 and/or promote Th1
responses during the early sensitization period was
expected to be a useful strategy to modulate the natural
course of atopic diseases [12].
Severe systemic fungal infections have become an
increasing problem during recent decades. The cell walls of
fungi are composed, primarily, of carbohydrates, including
mannoprotein, -glucan, and chitin, which can be
recognized by several classes of pattern recognition receptors
[13]. Among these, dectin-1, a C-type lectin receptor
involved in the recognition of -glucan was shown to be
crucial for the control of fungal infection [14,15]. Dectin-1
signaling in macrophages and neutrophils can trigger
phagocytosis, a respiratory burst, and the production of
inflammatory cytokines and chemokines, which further
activate macrophages and neutrophils, thus resulting in
the elimination of microorganisms [16]. Moreover, these
pattern recognition receptors can drive the development
of adaptive immunity. For example, signaling through
dectin-1 induces dendritic cell (DC) maturation with the
concomitant upregulation of co-stimulatory molecules
and the secretion of IL-2, IL-10, IL-6, and TNF-, in
addition to a bias for IL-23 production rather than IL-12
[17]. Dectin-1-activated DCs can instruct the
differentiation of Th1 and Th17, but not Th2 cells [17,18].
Stimulation of DCs via the dectin-1 pathway also allows priming
of cytotoxic T-cell responses [19].
Many fungi, such as Candida albicans, are both
commensals and pathogens at the skin surface and (...truncated)