Cyclic AMP in dendritic cells: A novel potential target for disease-modifying agents in asthma and other allergic disorders

Abstract

Allergic diseases are immune disorders that are a global health problem, affecting a large portion of the world's population. Allergic asthma is a heterogeneous disease that alters the biology of the airway. A substantial portion of patients with asthma do not respond to conventional therapies; thus, new and effective therapeutics are needed. Dendritic cells (DCs), antigen presenting cells that regulate helper T cell differentiation, are key drivers of allergic inflammation but are not the target of current therapies. Here we review the role of dendritic cells in allergic conditions and propose a disease-modifying strategy for treating allergic asthma: cAMP-mediated inhibition of dendritic cells to blunt allergic inflammation. This approach contrasts with current treatments that focus on treating clinical manifestations of airway inflammation. Disease-modifying agents that target cAMP and its signalling pathway in dendritic cells may provide a novel means to treat asthma and other allergic diseases.

FIGURE 1

Dendritic cell induction of Th2 differentiation and contribution of Th2 cytokines to asthma pathology. (a) Dendritic cells process and present antigens (allergens) on MHC class II molecules (MHC‐II) to naïve helper T cells. When naïve helper T cells bind to their cognate antigen presented on MHC‐II, they become activated and can differentiate into Th2 cells in the presence of IL‐4. (b) Activated Th2 cells secrete IL‐4, IL‐5, and IL‐13 which promote eosinophil migration and survival, increased mucus production, airway hyperresponsiveness, and IgE isotype class switching in B cells. IgE class switching leads to IgE production and results in mast cell degranulation and release of histamine

FIGURE 2

The cAMP signalling pathway. Upon ligand binding to G_s‐coupled GPCRs, the Gα_s protein activates adenylyl cyclases (AC) to catalyse the conversion of ATP to cAMP. The Gα_I protein inhibits AC, resulting in lower cAMP levels. cAMP primarily mediates its effects via PKA and/or Epac. PKA phosphorylates CREB which binds to CRE sites in the promoter of CREB‐responsive genes. A‐kinase anchoring proteins (AKAPs) localize enzymes to their signalling substrates in subcellular locations. cAMP is removed via degradation by phosphodiesterases (PDEs) or effluxed out by the transporter MRP4/ABCC4. Regulators of G protein signalling (RGS) proteins accelerate the hydrolysis of GTP to GDP of heterotrimeric G proteins and thus help terminate G protein activation. Numerous RGS proteins have been identified (O'Brien, Wilkinson, & Roman, 2019). The figure hypothesizes an as‐yet not definitively identified RGS protein for Gα_s. Multiple transcription factors, including IRF4, are downstream of and regulated by the cAMP pathway

FIGURE 3

Contribution of cAMP concentrations in dendritic cells to Th2 differentiation. ΔGnas mice, which have lower cAMP levels in their dendritic cells (DCs), have increased serum IgE, increased eosinophils present in bronchoalveolar lavage fluid, and airway hyperreactivity. Isolated dendritic cells from ΔGnas mice also preferentially induce naïve helper T cells (Th cells) to differentiate into Th2 cells. Dendritic cells from control (fl/fl) mice do not preferentially induce naïve helper T cells to differentiate into a particular T cell subset (Lee et al., 2015)