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Alarming inflammation: The TGFβ1–Nrp1 pathway upregulates the IL‐33 axis in lung ILC2s

Innate lymphoid cells (ILCs) are the most recently described population of innate immunity lymphocytes that patrol peripheral tissues. ILCs develop in the bone marrow and, based on their effector functions, can be divided into distinct subpopulations, mirroring the classification of T helper (Th) cells. Like Th2 cells, ILC2s express GATA3 and exploit their effector function mainly producing IL13 and IL5.1 ILC2s are rapidly activated upon stimulation by epitheliumderived cytokines such as TSLP, IL33, and IL25. ILC2s cooperate with other components of innate and adaptive immunity to provide a firstline defense against pathogens, but they can also sustain the development of immunemediated diseases such as allergic disorders and pulmonary fibrosis.1 ILC2s have become an appealing cell target to fight type 2 immunityrelated diseases and several therapeutic approaches are now under consideration, mainly neutralizing type 2 effector cytokines or epitheliumderived cytokines. In this view, Zhang et al. have recently discovered that lungresident ILC2s are highly sensitive to IL33. In fact, high TGFβ1 levels increase neuropilin1 (Nrp1) expression on ILC2s in the lungs and this induction is tissuespecific.2 Indeed, up to 80% of lungresident ILC2s express Nrp1, while it is rarely expressed by pancreatic and intestinal ILC2s.2 The TGFβ1– Nrp1 pathway in turn upregulates the IL33 receptor ST2, thus enhancing ILC2s' sensitivity to IL33 and driving the ILC2’s inflammatory phenotype.2 For this reason, multiple approaches aimed at suppressing this pathway may be beneficial in allergic diseases and particularly in type 2 asthma. Zhang et al. showed that smallmolecule inhibitors of TGFβ1 receptor signaling abolished the induction of Nrp1 by TGFβ1.2 TGFβ has been proposed as a potential therapeutic target in asthma because of its central role in airway remodeling. Selective targeting of TGFβ1 via neutralizing monoclonal antibodies (mAbs) may suppress the TGFβ1– Nrp1 pathway in lungresident ILC2s, thereby controlling inflammation. Notably, antiTGFβ1 mAbs reduced allergeninduced airway inflammation in preclinical models.3 Taking into account Nrp1, this molecule is also expressed by CD45RO+ ILC3s that display in vitro lymphoid tissue inducer (LTi) activity. These cells are present in lymphoid tissues but also in ectopic pulmonary lymphoid aggregates that are typically found in the lungs of smokers, asthmatics, and COPD patients.4 Such findings suggest that Nrp1 inhibition may contemporary target both lung ILC2s and LTilike ILC3s, exerting a potential favorable effect in patients with inflammationinduced pulmonary lymphoid aggregates. However, since Nrp1 has wide tissue expression its inhibition might not be a practicable therapeutic strategy. On the contrary, the IL33 axis is undergoing extensive studies in asthma, especially considering the central role of this pathway in childhood asthma. AntiIL33 mAbs (itepekimab, etokimab, and tozorakimab) and antiST2 mAbs (astegolimab and melrilimab) have been developed and are under clinical investigation.5 Itepekimab increased disease control and slightly improved lung function in moderatetosevere asthma without any appreciable differences when compared to dupilumab, an antiIL4Rɑ