Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma

Abstract

The inductive role of dendritic cells (DC) in Th2 differentiation has not been fully defined. We addressed this gap in knowledge by focusing on signaling events mediated by the heterotrimeric GTP binding proteins Gαs, and Gαi, which respectively stimulate and inhibit the activation of adenylyl cyclases and the synthesis of cAMP. We show here that deletion of Gnas, the gene that encodes Gαs in mouse CD11c + cells (Gnas ΔCD11c mice), and the accompanying decrease in cAMP provoke Th2 polarization and yields a prominent allergic phenotype, whereas increases in cAMP inhibit these responses. The effects of cAMP on DC can be demonstrated in vitro and in vivo and are mediated via PKA. Certain gene products made by Gnas ΔCD11c DC affect the Th2 bias. These findings imply that G protein-coupled receptors, the physiological regulators of Gαs and Gαi activation and cAMP formation, act via PKA to regulate Th bias in DC and in turn, Th2-mediated immunopathologies.cAMP | dendritic cells | Th2 | PKA | asthma

The Methyl-CpG-Binding Protein Mbd2 Regulates Susceptibility to Experimental Colitis via Control of CD11c+ Cells and Colonic Epithelium

“…Two other genes significantly upregulated in Mbd2 −/− cDC1s were Gipc1 and Adcy4 (Figures 3A,B), both of which can increase cellular cAMP 65−67 . Increases in cAMP can interfere with DC induction of Th2 responses, reduce MHC-II production and impair antigen presentation capabilities (27,42). However, future dedicated investigation and validation of the function of these genes in DCs, and determining whether these are regulated by the action of Mbd2, may shed light on the downstream mechanisms that influence intestinal pathology during colitis.…”

“…Ets2, the most significantly upregulated locus in Mbd2 −/− cDC1s, is a transcriptional regulator that increases expression of miR-155, a potent pro-inflammatory mediator found at increased levels in IBD mucosa (25,26). Gipc1 and Adcy4, also significantly upregulated in Mbd2 −/− DCs, encode a GTPase activator protein for Gαi/Gαq and adenylate cyclase enzyme, respectively, both of which can increase DC cAMP levels (27). Of the genes downregulated in Mbd2 −/− DCs, Nab1, and Itgae (CD103) may affect CEC function by reducing STAT5 and E-cadherin signaling, respectively, that may predispose to epithelial barrier breakdown (28,29).…”

Stability of regulatory T cells in T helper 2–biased allergic airway diseases

“…However, further studies are needed to investigate whether the intrinsic role of GATA3 in tTreg cell stability can be Notably, decreased cAMP in dendritic cells was recently reported to provoke the Th2 immune response in mouse asthma models. 54 Consequently, inhibition of cAMP degradation by a PKA-selective cAMP agonist in dendritic cells favored the Th2 response elimination in these mice. 55 The kinase PIM1, constitutively active serine/threonine protein kinases, negatively regulates human in allergic rhinitis patients receiving sublingual immunotherapy.…”

Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses

“…Bronchoalveolar lavage (BAL) fluid was collected for cellular composition (light microscopy) and cytokine analysis. For cytokine analysis from lung tissue, lung single cell suspension was prepared from three lobes from each mouse as described (Doherty et al, 2011;Lee et al, 2015) and stimulated with HDM (50 µg/ml) or OVA (200 µg/ml) for 3 days. Supernatant from the culture was applied to cytokine analysis by ELISA.…”