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. 2015 Jul 15;195(2):431-5.
doi: 10.4049/jimmunol.1500474. Epub 2015 Jun 10.

Cutting Edge: Dual Function of PPARγ in CD11c+ Cells Ensures Immune Tolerance in the Airways

Anupriya Khare  1 , Krishnendu Chakraborty  1 , Mahesh Raundhal  2 , Prabir Ray  2 , Anuradha Ray  3
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Cutting Edge: Dual Function of PPARγ in CD11c+ Cells Ensures Immune Tolerance in the Airways

Anupriya Khare et al. J Immunol. .

Abstract

The respiratory tract maintains immune homeostasis despite constant provocation by environmental Ags. Failure to induce tolerogenic responses to allergens incites allergic inflammation. Despite the understanding that APCs have a crucial role in maintaining immune tolerance, the underlying mechanisms are poorly understood. Using mice with a conditional deletion of peroxisome proliferator-activated receptor γ (PPARγ) in CD11c(+) cells, we show that PPARγ performs two critical functions in CD11c(+) cells to induce tolerance, thereby preserving immune homeostasis. First, PPARγ was crucial for the induction of retinaldehyde dehydrogenase (aldh1a2) selectively in CD103(+) dendritic cells, which we recently showed promotes Foxp3 expression in naive CD4(+) T cells. Second, in all CD11c(+) cells, PPARγ was required to suppress expression of the Th17-skewing cytokines IL-6 and IL-23p19. Also, lack of PPARγ in CD11c(+) cells induced p38 MAPK activity, which was recently linked to Th17 development. Thus, PPARγ favors immune tolerance by promoting regulatory T cell generation and blocking Th17 differentiation. VSports手机版.

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Figures

FIGURE 1
FIGURE 1
CD11c-specific PPARγ deficiency impairs airway tolerance induction. (A) Expression of pparg mRNA in CD103+ lung DCs from naïve, tolerized and OVA/CT mice, relative to hprt1. (B-I) PPAR γ fl/fl and from CD11c-Cre-PPAR γ fl/fl mice were tested for induction of tolerance as described. 24 hours after the last challenge, various parameters of inflammation were analyzed. (B) Histological assessment of lung sections after PAS staining. Scale bar, 100 µm and magnification 20X. (C) Total cells, (D) eosinophil (Eos) and neutrophil (Neu) numbers in the BALF (n=6). (E) OVA-specific serum IgE levels. (F) qRT-PCR analysis of gene expression in the lungs of mice subjected to the sequential tolerance and inflammation model, relative to expression in naïve mice. (G) Total and CD4+ T cell numbers (n=4) and (H) frequency of IL-17A- and IFN-γ-expressing lung CD4+ T cells in mice (n=6) subjected to indicated conditions. (I) Expression of transcription factors RORγt, GATA-3 and T-bet in lung CD4+ T cells from PPARγfl/fl and CD11c-Cre-PPARγfl/fl mice (n=6) subjected sequentially to tolerance and inflammation models. Numbers shown represent mean ± SEM mean fluorescence intensities (MFIs). Data in (A-B) and (E-F) are representative of two independent experiments and data in (C) and (G-I) are representative of three independent experiments; symbols in the graphs represent data from individual mice, horizontal lines show the mean and error bars denote SEM.
FIGURE 2
FIGURE 2
PPARγ deficiency in CD11c+ cells impairs de novo Foxp3 induction in CD4+ T cells and promotes expression of pro-inflammatory cytokines. (A) Representative flow cytometry data and number of de novo induced CD4+ Thy1.1+ Foxp3+ T cells in PPARγfl/fl and CD11c-Cre-PPARγfl/fl mice are shown. Symbols in the graphs represent data from individual mice; horizontal lines show the mean and error bars denote SEM (n=6 mice). (B) Expression of aldh1a2, Il6 and Il23a (p19) relative to that of hprt1. (C) Various CD11c+ cells subsets expressing IL-6 and IL-23p19 from naïve and tolerized CD11c-Cre-PPARγfl/fl and PPARγfl/fl mice (n=6 mice). Data shown are mean ± SEM of two independent experiments.
FIGURE 3
FIGURE 3
PPARγ deficiency in CD11c+ cells promotes p38 MAPK activity and CD86 expression. (A) Immunoprecipitated phospho-p38 from lung CD11c+ cells incubated with the substrate ATF-2 and phospho-ATF-2 was detected by immunoblotting as a measure of p38 MAPK activity. Total p38 MAP kinase was assessed to ensure equivalent protein loading. Bar graph represents densitometric quantification. (B) MHC II, CD80 and CD86 expression on various CD11c+ cell subsets. Numbers shown represent MFIs. Data shown are representative of two independent experiments.
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