Abstract
Fas–Fas ligand (FasL) signaling plays an important role in the development of allergic inflammation, but the cellular and molecular mechanisms are still not well known. By using the bone marrow-derived dendritic cell (BMDC) transfer-induced pulmonary inflammation model, we found that house dust mite (HDM)-stimulated FAS-deficient BMDCs induced higher Th2-mediated allergic inflammation, associated with increased mucus production and eosinophilic inflammation. Moreover, FAS-deficient BMDCs promoted Th2 cell differentiation upon HDM stimulation in vitro. Compared to wild-type BMDCs, the Fas-deficient BMDCs had increased ERK activity and decreased IL-12 production upon HDM stimulation. Inhibition of ERK activity could largely increase IL-12 production, consequently restored the increased Th2 cytokine expression of OT-II CD4+ T cells activated by Fas-deficient BMDCs. Thus, our results uncover an important role of DC-specific Fas signaling in Th2 differentiation and allergic inflammation, and modulation of Fas signaling in DCs may offer a useful strategy for the treatment of allergic inflammatory diseases.
Highlights
Allergic inflammation has been generally considered as a T helper (Th) 2-mediated chronic immune response [1]
The cell number of inflammatory eosinophils (iEos) was increased in recipients transferred with House dust mite (HDM)-pulsed Fas-deficient bone marrow-derived dendritic cell (BMDC) compared to those transferred with HDM-pulsed wild-type BMDCs, but resident eosinophils (rEos) was comparable between recipients transferred with HDM-pulsed wild-type BMDCs and those transferred with Fas-deficient BMDCs (Figure 1E)
We found that HDM-pulsed Fas-deficient BMDCs could promote Th2 responses and allergic eosinophilic inflammation, without affecting T cell apoptosis and proliferation in the recipients
Summary
Allergic inflammation has been generally considered as a T helper (Th) 2-mediated chronic immune response [1]. DC-FAS Suppresses Allergic Inflammation initiate Th2 responses, the underlying signaling mechanism for DCs to direct Th2 differentiation and function is still not wellunderstood. Further study indicates that Fas deficiency in T cells contributes to the prolonged resolution of airway inflammation [12]. Recent studies have shown that Fas–FasL interaction could activate nonapoptotic pathways, such as Fas signaling leading to T cell activation, proliferation and differentiation [13] and promoting Th17 polarization and Th17-mediated autoimmunity [14]. We used the well-established model by adoptively transferring HDM-pulsed BMDCs to recipient mice to explore the role of FAS signaling in DCs in pulmonary inflammation. We found that Fas deficiency in DCs led to increased mucus production, eosinophilic inflammation and Th2 response in vivo. Our results identify an important signaling mechanism of DC-mediated Th2 responses and modulation of Fas signaling in DCs might offer a useful strategy for the treatment of eosinophilic lung inflammatory diseases
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