TNF Superfamily and ILC2 Activation in Asthma

Abstract

Eosinophilic asthma is the most prevalent and well-defined phenotype of asthma. Despite a majority of patients responding to corticosteroid therapy and T2 biologics, there remains a subset that have recurrent asthma exacerbations, highlighting a need for additional therapies to fully ameliorate airway eosinophilia. Group 2 innate lymphoid cells (ILC2) are considered key players in the pathogenesis of eosinophilic asthma through the production of copious amounts of type 2 cytokines, namely IL-5 and IL-13. ILC2 numbers are increased in the airways of asthmatics and with the greatest numbers of activated ILC2 detected in sputa from severe prednisone-dependent asthma with uncontrolled eosinophilia. Although epithelial-derived cytokines are important mediators of ILC2 activation, emerging evidence suggests that additional pathways stimulate ILC2 function. The tumor necrosis factor super family (TNFSF) and its receptors (TNFRSF) promote ILC2 activity. In this review, we discuss evidence supporting a relationship between ILC2 and TNFSF/TNFRSF axis in eosinophilic asthma and the role of this relationship in severe asthma with airway autoimmune responses.

Keywords: GITRL; OX40L; RANKL; TL1A; TNF; TNFSF; airway autoimmune response; eosinophilic asthma; group 2 innate lymphoid cell.

Figure 1

Receptor Expression for TNF Super Family on ILC2. Legend: ILC2 expresses four distinct receptors for TNFSF, including TNFR2, RANK, GITR, and DR3, which bind to their respective ligands/mediators TNF, RANKL, GITRL, and TL1A. Moreover, ILC2 expresses OX40L upon stimulation with IL-33 to activate T cells by binding to OX40 on T cells. DR3 = Death Receptor 3; GITR = Glucocorticoid-induced Tumor Necrosis-Receptor-Related Gene; GITRL = Glucocorticoid-induced Tumor Necrosis-Receptor-Related Gene Ligand; ILC2 = Group 2 Innate Lymphoid Cell; RANK = Receptor Activator of Necrosis Factor Kappa B; RANKL = Receptor Activator of Necrosis Factor Kappa B Ligand; TL1A = Tumor Necrosis Factor-like Ligand 1A; TNF = Tumor Necrosis Factor; TNFR2 = Tumor Necrosis Factor Receptor 2; TNFRSF = Tumor Necrosis Factor Receptor for Super Family; TNFSF = Tumor Necrosis Factor Super Family.

Figure 2

The role of ILC2 in corticosteroid resistant vs. sensitive asthma. Legend: Airway epithelium damage by allergens releases IL-25, IL-33 and TSLP to activate ILC2, inducing airway eosinophilic inflammation. Treatment with corticosteroids has many effects including directly acting on ILC2 to induce apoptosis and suppress airway eosinophilic inflammation (right). In contrast, in situations with high airway levels of IL-25, IL-33 and TSLP, autoantibodies to eosinophil-derived granule proteins form immune complexes that stimulate TL1A production by macrophages; TL1A then further promotes type 2 cytokine production from ILC2 via ligation of DR3. Consequently, a potent ILC2-driven airway eosinophilic inflammation, not suppressed by treatment with high-dose corticosteroids, is established. Therefore, in combination with TSLP, TL1A drives ILC2 insensitivity to corticosteroids (left). DR3 = Death Receptor 3; ECP = Eosinophil Cationic Protein; EDN = Eosinophil-Derived Neurotoxin; EPX = Eosinophil Peroxidase; TL1A = Tumor Necrosis Factor-like Ligand 1A; TSLP = Thymic Stromal Lymphopoietin.