Prostaglandin D2 Signaling in Allergy and Asthma

Prostaglandin D2 (PGD2) is a bioactive lipid produced predominantly by mast cells and, to a lesser extent, by TH2 cells, dendritic cells and eosinophils following activation of the cyclooxygenase pathway. In the airway, PGD2 orchestrates allergic inflammation through two distinct G-protein-coupled receptors, DP1 and DP2. Engagement of DP2 (also known as CRTH2) on TH2 cells, type-2 innate lymphoid cells (ILC2s), eosinophils and CD8+ Tc2 cells drives chemotaxis, degranulation and type-2 cytokine release, thereby promoting airway eosinophilia, mucus overproduction and bronchial hyper-responsiveness. In contrast, DP1 activation can counter-regulate inflammation and support epithelial repair, partly through induction of interferon-γ. Imbalances between DP1- and DP2-mediated pathways underpin airway remodelling, exacerbation susceptibility and variable responses to corticosteroids. Targeting components of the PGD2 axis has therefore emerged as a strategy to modulate type-2 inflammation in asthma and allergic disorders, although clinical efficacy has been tempered by compensatory signalling and interactions with standard anti-inflammatory therapies.

Research from Nature Portfolio

In a preclinical model of chronic asthma exacerbated by rhinovirus, heightened PGD2 release was shown to drive airway remodelling, mucus secretion, transforming growth factor-β1 production and type-2 inflammation. Selective antagonism of DP2 or agonism of DP1 ablated these phenotypes by restoring epithelial epidermal growth factor expression and upregulating interferon-γ, resulting in reduced airway smooth muscle mass. By contrast, dual blockade of DP1 and DP2, or concomitant corticosteroid/DP2 antagonism, suppressed endogenous PGD2 and interferon-γ and impaired resolution of remodelling, providing a mechanistic explanation for mixed outcomes in late-phase clinical trials of DP2 antagonists. An earlier foundational study demonstrated that genetic ablation of haematopoietic prostaglandin D synthase exacerbates antigen-induced mast cell hyperplasia and allergic symptoms in the intestine. Loss of PGD2 synthesis accelerated stromal-derived factor-1α production and matrix metalloproteinase-9 activity, amplifying mast cell accumulation and allergic pathology. This work highlighted a homeostatic, anti-proliferative role for mast cell–derived PGD2 in restraining allergic tissue remodelling.

Prostaglandin D2 Signaling in Allergy and Asthma publication trend

The graph below shows the total number of articles in prostaglandin d2 signaling in allergy and asthma across all publications each year (not limited to Nature Index journals).

Technical terms

Prostaglandin D2 (PGD2): A cyclooxygenase-derived lipid mediator involved in the initiation and modulation of allergic inflammation and bronchial hyper-responsiveness.

DP1 receptor: A G-protein-coupled receptor for PGD2 that mediates anti-inflammatory effects and supports epithelial repair in the airway.

DP2 receptor (CRTH2): A G-protein-coupled receptor expressed on TH2 cells, ILC2s, eosinophils and Tc2 cells; drives chemotaxis and type-2 cytokine secretion upon PGD2 binding.

Haematopoietic PGD synthase (hPGDS): The enzyme in immune cells that converts PGH2 to PGD2, critically regulating PGD2 availability in allergic responses.

Type 2 innate lymphoid cells (ILC2): Innate immune cells producing IL-5 and IL-13, recruited and activated by PGD2 via DP2 to amplify airway eosinophilia and mucus production.

References

1. Dual therapy with corticosteroid ablates the beneficial effect of DP2 antagonism in chronic experimental asthma. Nature Communications (2024).
2. PGD2 deficiency exacerbates food antigen-induced mast cell hyperplasia. Nature Communications (2015).
3. Phospholipid scramblase-1 regulates innate type 2 inflammation in mouse lung via CRTH2-dependent mechanisms. Journal of Clinical Investigation (2023).
4. Synergistic activation of pro-inflammatory type-2 CD8+ T lymphocytes by lipid mediators in severe eosinophilic asthma. Mucosal Immunology (2018).