*3.3. Innate Allergic Inflammation and Group 2 Innate Lymphoid Cells (ILC2s)*

ILC2s are tissue-resident cells that do not express T-cell, B-cell, or monocytic markers; however, they are able to produce Th2 cytokines, namely IL-5 and IL-13, at a markedly higher level than CD4+ Th2 cells [3]. ILC2s are instrumental in amplifying allergic inflammation in the lung [2].

In order to determine the effect of endogenous IP signaling on ILC2 function, mice were challenged with 4 consecutive days of *Alternaria* extract (Alt Ex) to elicit inflammation by innate immunity that precedes significant contribution from the adaptive immune response. In Alt Ex-challenged IP KO mice, there was an increase in lung IL-5 and IL-13 expression, as well as heightened airway eosinophilia and mucus compared to Alt Ex-challenged WT

mice [2]. This revealed that endogenous IP signaling restrains ILC2-induced inflammation. In addition to these in vivo findings, in vitro data revealed that cicaprost inhibited IL-5 and IL-13 protein expression by IL-33-stimulated mouse ILC2s [2]. Likewise, in human ILC2s, cicaprost dose-dependently decreased IL-33-induced IL-5 and IL-13 production [2]. Others have reported similar findings. In a study examining mice stimulated with intranasal IL-33, the iloprost-treated group had lower mRNA expression levels of IL-5 and IL-13 alongside a reduction in the proliferation of ILC2s relative to mice treated with the vehicle for iloprost, demonstrating the attenuating effects of prostacyclin analogs on ILC2 type 2 cytokine production [26]. These findings were supported by another study that reported that iloprost directly suppressed ILC2 cytokine production following IL-33 activation [27].
