Dectin-2 Regulates the Effector Phase of House Dust Mite–Elicited Pulmonary Inflammation Independently from Its Role in Sensitization

Abstract

The myeloid C-type lectin receptor Dectin-2 directs the generation of Th2 and Th17 immune responses to the house dust mite Dermatophagoides farinae (Df) through the generation of cysteinyl leukotrienes (cys-LTs) and pro-inflammatory cytokines, respectively, but a role for Dectin-2 in effector phase responses has not been described. Here, we demonstrate that administration of the Dectin-2 mAb solely at the time of Df challenge abrogated eosinophilic and neutrophilic inflammation in the bronchoalveolar lavage (BAL) fluid and Th1, Th2, and Th17 inflammation in the lung of previously sensitized mice. Furthermore, Dectin-2 null mice (Clec4n−/−) sensitized with the adoptive transfer of Df-pulsed wild-type (WT) bone marrow-derived DCs (BMDCs) also had less Df-elicited pulmonary inflammation, supporting an effector function for Dectin-2. The protection from pulmonary inflammation seen with the Dectin-2 mAb or in Clec4n−/− mice was associated with little or no reduction in lung-draining lymph node cells or their cytokine production, and with no reduction in serum IgE. WT and Clec4n−/− mice recipients, sensitized with Df-pulsed WT BMDCs, had comparable levels of Df-elicited IL-6, IL-23, TNF-α, and cys-LTs in the lung. By contrast, Df-elicited CCL4 and CCL8 production from pulmonary CD11c+CD11b+Ly6C+ and CD11c+CD11b+Ly6C−CD64+ monocyte-derived DCs was reduced in Clec4n−/− recipients. Addition of CCL8 at the time of Df challenge abrogated the protection from eosinophilic, neutrophilic, and Th2 pulmonary inflammation seen in Clec4n−/− recipients. Taken together, these results reveal that Dectin-2 regulates monocyte-derived DC function in the pulmonary microenvironment at Df challenge to promote the local inflammatory response.

Opposing Roles of Dectin-1 Expressed on Human Plasmacytoid Dendritic Cells and Myeloid Dendritic Cells in Th2 Polarization

“…However, curdlan treatment on pDCs did not induce Cys-LT secretion (Fig. 2H), although house dust mite Df extract stimulated pDCs to secrete increased amount of Cys-LT, which can drive Th2 responses (27, 32). …”

C-type lectin receptors in the control of T helper cell differentiation

“…Furthermore, dectin 2 signalling in mouse cells indirectly enhances dectin 1-dependent T H 1 cell responses in response to fungal PAMPs, but it remains to be determined which cytokines are involved in this effect 69,70 . Mouse dectin 2 has also been shown to interact with glycans on allergens from Aspergillus fumigatus and the house dust mites Dermatophagoides farinae and Dermatophagoides pteronyssinus, thereby inducing signals that skew T H cell differentiation towards T H 2 cell responses [73][74][75] (TABLE 1). Recognition of D. farinae allergens by dectin 2 leads to SYK-dependent cysteinyl leukotriene production 74,75 , which can counteract the induction of IL-12 expression 76 , thereby inducing T H 2 cell responses 74 (FIG.…”

“…4a). Notably, sensitization of dectin 2-deficient mice with D. farinae allergens did not induce eosinophilic and neutro philic pulmonary inflammation or T H 2 cell responses in lymph nodes and lungs 73 . Thus, dectin 2-mediated control of T H cell differentiation in mice varies with pathogen species and ligand, and this variation might be harnessed to direct immunological responses during vaccine design.…”

“…Downstream signalling leads to the activation of nuclear factor-κB (NF-κB) p65-containing complexes, which in turn results in the expression of the T helper 17 (T H 17)-polarizing cytokines pro-interleukin-1β (pro-IL-1β), IL-6 and IL-23. By contrast, in a SYK-dependent manner, dectin 2 recognition of allergens leads to the generation of cysteinyl leukotrienes (Cys-LTs), which skews T H cell differentiation towards pathogenic T H 2 cell responses[73][74][75] , possibly by blocking the expression of IL-12 induced by other pattern-recognition receptors (PRRs) such as Toll-like receptors (TLRs)76 . b | In humans, activation of dectin 2 by fungi leads to FcRγ signalling via SHP2-SYK and the CARD9-BCL-10-MALT1 scaffold36,77 .…”

International Union of Basic and Clinical Pharmacology. XCVI. Pattern Recognition Receptors in Health and Disease

“…Dectin-2 is also involved in the generation of both Th1 and Th17 responses to Candida glabrata (Ifrim et al, 2014) and it contributes to C. albicans-induced Th1 responses in collaboration with Dectin-1 (Robinson et al, 2009;Saijo et al, 2010). In addition to its role in antifungal responses, Dectin-2 also induces allergic inflammation in response to house dust mites through the production of cysteinyl leukotrienes and subsequent development of Th2 and Th17 responses (Barrett et al, 2011;Clarke et al, 2014;Norimoto et al, 2014;Parsons et al, 2014). Interestingly, Dectin-2 is also involved in regulating an autocrine IL-17 loop that controls the activation of a subset of neutrophils (Taylor et al, 2014).…”