A Potential Role for P2X₇R in Allergic Airway Inflammation in Mice and Humans

Abstract

P2X₇R deficiency is associated with a less severe outcome in acute and chronic inflammatory disorders. Recently, we demonstrated that extracellular adenosine triphosphate is involved in the pathogenesis of asthma by modulating the function of dendritic cells (DCs). However, the role of the purinergic receptor subtype P2X₇ is unknown. To elucidate the role of P2X₇R in allergic airway inflammation (AAI) in vitro and in vivo, P2X₇R expression was measured in lung tissue and immune cells of mice or in humans with allergic asthma. By using a specific P2X₇R-antagonist and P2X₇R-deficient animals, the role of this receptor in acute and chronic experimental asthma was explored. P2X₇R was found to be up-regulated during acute and chronic asthmatic airway inflammation in mice and humans. In vivo experiments revealed the functional relevance of this finding because selective P2X₇R inhibition or P2X₇R deficiency was associated with reduced features of acute and chronic asthma in the ovalbumin-alum or HDM model of AAI. Experiments with bone marrow chimeras emphasized that P2X₇R expression on hematopoietic cells is responsible for the proasthmatic effects of P2X₇R signaling. In the DC-driven model of AAI, P2X₇R-deficient DCs showed a reduced capacity to induce Th2 immunity in vivo. Up-regulation of P2X₇R on BAL macrophages and blood eosinophils could be observed in patients with chronic asthma. Our data suggest that targeting P2X₇R on hematopoietic cells (e.g., DCs or eosinophils) might be a new therapeutic option for the treatment of asthma.

P2X7 receptor antagonism attenuates the hypertension and renal injury in Dahl salt-sensitive rats

“…DISCUSSION P2X 7 is recognized as one of the key factors in the modulation of inflammatory processes. 2,3,25 Indeed, P2X 7 has recently been reported to be involved in various inflammatory processes of different pathological conditions, such as cerebral infarction 26 or ischemia, 27,28 lung inflammation and emphysema, 29 allergic airway inflammation, 30 unilateral urethral obstructive nephropathy 9 and accelerated nephrotoxic nephritis. 10 Several recent studies have provided convincing evidence that the renal proinflammmatory response has an important role in mediating salt-sensitive hypertension.…”

Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration

“…Another study demonstrated that this allergic inflammation in humans and mice is associated with the functional up-regulation of P2X7 receptor expression on immune cells (macrophages and eosinophils) and that P2X7 receptor signaling (e.g., via modulating of DC function) is involved in ATP-mediated pro-asthmatic effects [136]. P2X7 receptor −/− knock-out animals or animals treated with a selective P2X7 receptor antagonist showed a strong reduction in all cardinal features of acute allergic airway inflammation including airway eosinophilia, goblet cell hyperplasia, and bronchial hyperresponsiveness to methacholine [137]. Thus, P2X7 receptor antagonists might be a new therapeutic option for the treatment of severe asthma.…”

P2X7 Receptor-Dependent Intestinal Afferent Hypersensitivity in a Mouse Model of Postinfectious Irritable Bowel Syndrome

“…For example, in models of chronic inflammatory airway disease, P2X 7 R expression is increased on human and mouse macrophages/dendritic cells (18,19). P2X 7 R antagonists were shown to decrease the inflammatory response in an animal model of arthritis (20), and P2X 7 R knockout mice possess reduced inflammatory thermal hyperalgesia and nerve injury-induced mechanical allodynia (21).…”