Asthma is a chronic respiratory disease that is characterized by airway inflammation and non-specific bronchial hyperresponsiveness resulting in airway obstruction. Airway inflammation is initiated at mucosal surfaces where inhaled allergens contact the lung epithelium. While common allergens, such as house dust mite (HDM), papain, and Alternaria alternata, are heterogeneous, a common component of these allergens is molecules with protease activity. Proteases in inhaled allergens damage the epithelial barrier and trigger the production of interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP) from cells residing in the epithelium [1], [2], [3], [4]. These epithelial-derived cytokines activate tissue-resident immune cells including group 2 innate lymphoid cells (ILC2) that produce IL-5 and IL-13 [5], [6], [7], [8], [9], [10]. Inhalation of papain, a plant-derived cysteine protease, has been shown to cause occupational asthma in humans [11]. Intranasal administration of papain in mice triggers the activation of ILC2s and the induction of eosinophilia in the lungs in an IL-33-dependent manner [5].

Diacylglycerol kinases (DGK) are a family of enzymes that convert diacylglycerol (DAG) to phosphatidic acid (PA) via phosphorylation to terminate DAG-mediated signaling [12], [13]. There are 10 different isoforms comprising 5 different classes of DGKs, each of which control different cellular functions based on their distinct structural motifs and subcellular localization [12], [13], [14], [15], [16]. The zeta isoform of DGK (DGKζ) is widely expressed in the hematopoietic and non-hematopoietic compartments and is important for regulating diverse cellular processes in both of these compartments [17]. Previously, we demonstrated that DGKζ plays an immunomodulatory role in type 2 immune responses by positively controlling Th2 differentiation through the regulation of TCR-mediated ERK signaling to promote type 2 airway inflammation [18]. Furthermore, the loss of DGKζ has been shown to attenuate FcεRI-mediated degranulation of mast cells and consequently, DGKζ KO mice display impaired IgE-mediated anaphylactic responses in vivo [19]. However, whether DGKζ plays an immunomodulatory role in ILC2-mediated inflammatory responses is unknown.

Here, we report that the loss of DGKζ protects from papain-induced type 2 airway inflammation in mice. Papain-challenged DGKζ knockout (KO) mice displayed reduced ILC2 accumulation, decreased IL-5 and IL-13 release, and attenuated lung eosinophilia. Unexpectedly, mice with hematopoietic cell-specific deletion of DGKζ displayed intact papain-induced airway inflammation. Bone marrow chimera studies revealed that DGKζ deficiency in the non-hematopoietic compartment was responsible for the reduction in papain-induced airway inflammation. Thus, DGK deficiency attenuates ILC2-dependent allergic airway inflammation cell-extrinsically through non-hematopoietic cells.