Lipoxin A ₄ Regulates Natural Killer Cell and Type 2 Innate Lymphoid Cell Activation in Asthma

Abstract

Asthma is a prevalent disease of chronic inflammation in which endogenous counter-regulatory signaling pathways are dysregulated. Recent evidence suggests that innate lymphoid cells (ILCs), including natural killer (NK) cells and type 2 innate lymphoid cells (ILC2), can participate in the regulation of allergic airways responses, in particular airway mucosal inflammation. Here, we have identified both NK cells and ILC2 in human lung and peripheral blood in healthy and asthmatic subjects. NK cells were highly activated in severe asthma, linked to eosinophilia and interacted with autologous eosinophils to promote their apoptosis. ILC2 generated antigen-independent IL-13 in response to the mast cell product prostaglandin D2 (PGD2) alone and in a synergistic manner with the airway epithelial cytokines IL-25 and IL-33. Both NK cells and ILC2 expressed the pro-resolving ALX/FPR2 receptors. Lipoxin A4, a natural pro-resolving ligand for ALX/FPR2 receptors, significantly increased NK cell mediated eosinophil apoptosis and decreased IL-13 release by ILC2. Together, these findings indicate that ILCs are targets for lipoxin A4 to decrease airway inflammation and mediate the catabasis of eosinophilic inflammation. Because lipoxin A4 generation is decreased in severe asthma, these findings also implicate unrestrained ILC activation in asthma pathobiology.

Group 2 Innate Lymphoid Cells in Health and Disease

“…Further, ILC2s have also recently been shown to respond directly to non-cytokine molecules, including eicosanoids. Specifically, ILC2s are activated by prostaglandin D 2 (PGD 2 ) (Barnig et al 2013;Chang et al 2013;Xue et al 2013) and leukotriene D 4 (LTD 4 ) and are inhibited by lipoxin A 4 (LXA 4 ) (Barnig et al 2013). In addition to activation, human ILC2s express the PGD 2 receptor chemoattractant receptor-homologous molecule expressed on T H 2 cells (CRTH2) and migrate in vitro in response to PGD 2 (Chang et al 2013;Xue et al 2013).…”

“…A recent study has shown that TSLP can contribute to ILC2 activation that promotes corticosteroid resistance in the context of IL-33-mediated airway inflammation (Kabata et al 2013). Further, recent reports suggest that other factors, such as eicosanoids, could also play a key role in promoting ILC2 responses in the inflamed lung (Barnig et al 2013;Doherty et al 2013). For instance, lung ILC2s express the receptor for LTD 4 and ligation of this receptor rapidly induces IL-5 production by ILC2s.…”

“…In the same study, LTD 4 , but not IL-33, induced high levels of IL-4 production by ILC2s . Furthermore, in vitro studies have shown that PGD 2 derived from mast cells activates ILC2s, up-regulates expression of receptors for IL-25 (IL-17RA) and IL-33 (ST2), and induces chemotaxis of human ILC2s (Barnig et al 2013;Chang et al 2013;Xue et al 2013). Furthermore, LXA 4 , a proresolving factor known to be decreased in severe asthma, directly inhibited PGD 2 -mediated activation of human ILC2s from peripheral blood ).…”

Type-2 Innate Lymphoid Cells in Asthma and Allergy

“…Notably, the leukotriene inhibitor montelukast can inhibit cytokine production by both mouse and human ILC2 (52,54), suggesting that part of the therapeutic effect of this drug in asthma may be due to blocking ILC2 activation. Notably, human ILC2 also express the pro-resolvin receptor ALX/FRP2, which binds the resolving lipoxin A 4 (51). Like leukotrienes and prostaglandins, lipoxin A 4 is derived enzymatically from arachidonic acid.…”

Les cellules lymphoïdes innées

“…En outre, des essais cliniques de blocage de l'IL-13 par un anticorps monoclonal, menés chez des patients asthmatiques, ont montré une efficacité relative [18]. Les ILC1 (NK) et les ILC2 pourraient également intervenir dans l'asthme via l'induction de l'apoptose des éosinophiles par les NK et la production d'IL-13 par les ILC2, ces deux mécanismes étant régulés par la lipoxine A4 [19]. Le rôle des ILC2 dans la progression de ces pathologies reste néanmoins à déterminer.…”