Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells

Nat Med. 2007 Aug;13(8):913-919

Speaker： Yi-Shung Chen (陳怡璇)                  Time：15：00~16：00, Nov. 21, 2007

Commentator： Dr. Jiu-Yao Wang (王志堯 醫師)     Place：Room 601

Abstract：

Allergic asthma is a Th2 lymphocyte-associated inflammatory airway disease characterized mainly by eosinophilic airway inflammation, Th2 cytokine production, variable airway obstruction and bronchial hyper-reactivity. Various cell types including eosinophils, mast cells, T lymphocytes, antigen-presenting dendritic cells (DCs) and numerous inflammatory mediators are involved in allergic inflammation. Previous studies have shown that myeloid DCs (mDCs) play an essential role in inducing effector cytokines production in the primed Th2 cells during airway inflammation¹. Another research suggested that extracellular ATP and its enzymatically breakdown products act as the inflammatory mediators², alerting the immune system by binding with P2X or P2Y receptors (P2Rs)³. In this study, the authors observed that the ATP levels were elevated in the bronchoalveolar lavage fluid (BALF) of asthmatic patients and mice. Further, the main features of asthma were abrogated in ovalbumin (OVA)-sensitized mice by treating with apyrase, an ATP hydrolyzing enzyme, or suramin, a broad-range inhibitor of P2Rs. They also found that mice treated with OVA and ATPγS, a non-hydrolyzable ATP analog, caused DCs recruitment and migration to the lung and mediastinal lymph nodes (MLNs). In addition, mice received OVA-pulsed mDCs pretreated with ATPγS can enhance eosinophilic airway inflammation, accompanied by an increase in Th2 cytokines in MLNs, while treatment with suramin at the same time interfered with this ability of mDCs. These results showed that ATP can enhance the capability of mDCs to prime for Th2 responses directly. Therefore, the extracellular ATP has a key role in allergen-driven lung inflammation by activating mDCs, and it may be used as a target for therapeutic intervention to suppress asthmatic inflammation.

References：

1. Van Rijt, L.S. et al. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J. Exp. Med. 201, 981–991 (2005).

2. Adriaensen, D. and Timmermans, J.P. Purinergic signalling in the lung: important in asthma and COPD? Curr. Opin. Pharmacol. 4, 207–214 (2004).

3. Khakh, B.S. and North, R.A. P2X receptors as cell-surface ATP sensors in health and disease. Nature 442, 527–532 (2006).