Notch Signaling Orchestrates Helminth-Induced Type 2 Inflammation

Abstract

Infection with helminth parasites poses a significant challenge to the mammalian immune system. The type 2 immune response to helminth infection is critical in limiting worm-induced tissue damage and expelling parasites. Conversely, aberrant type 2 inflammation can cause debilitating allergic disease. Recent studies have revealed that key type 2 inflammation-associated immune and epithelial cell types respond to Notch signaling, broadly regulating gene expression programs in cell development and function. Here, we discuss new advances demonstrating that Notch is active in the development, recruitment, localization, and cytokine production of immune and epithelial effector cells during type 2 inflammation. Understanding how Notch signaling controls type 2 inflammatory processes could inform the development of Notch pathway modulators to treat helminth infections and allergies.

Keywords: Notch; Type 2; adaptive; allergy; helminth; innate.

Figure 1.. Notch receptor activation drives rapid transcription of Notch target genes.

Ligation of a mammalian Notch receptor (Notch 1–4) by a Notch ligand (Delta/Jagged) on the cell surface (various cell types) leads to intracellular cleavage of the Notch intracellular domain (NICD) by a γ secretase enzyme. The NICD then translocates to the nucleus, where it forms a transcription-activating complex composed of the transcription factor Rbpj (also known as CSL in humans), various accessory proteins and co-activators (CoA) and Mastermind-like (MAML) proteins. This complex binds to Notch target sites across the genome to induce transcription of Notch target genes.

Figure 2.. The role of the Notch pathway in human and mouse Th2 cell development and function.

Notch signaling plays a role in T helper type 2 (Th2) cell polarization and maintenance by affecting a variety of processes during Type 2 inflammation. Conventional dendritic cells (cDCs) in mucosal tissue are exposed to antigens during Type 2 inflammation, in this case, helminth infection in the intestine. This includes Type 2-associated antigens (Type 2-Ag), including helminth Ag, and those that induce Type 1 responses (Type 1-Ag), such as those from bacteria or viral species. Type 2-Ag and Type 1-Ag drive upregulation of Jagged and Delta ligands on cDCs, respectively. cDCs traffic to the draining lymph node (dLN) and interact with naïve CD4⁺ T cells. Jagged upregulation on cDCs may support a Th2 cell fate by activating Gata3 and Il4 expression downstream of Notch. Delta ligands expressed by cDCs may inhibit Th2 priming and induce a Th1 cell fate by inhibiting Il4 expression and driving Ifng induction. Notch ligands are also expressed in the dLN by non-hematopoietic cells, including structural cell populations such as stromal fibroblasts. Exposure to Notch ligands on these cells may drive expression of functional genes and induce migration to inflamed tissue. Further exposure to Notch ligands in the periphery or inflamed tissue (such as the intestine) may also help to maintain a Th2 cell fate by promoting continued Gata3 and Il4 expression [54]. The exact location and ligand-bearing cell(s) in this interaction are not known. Notch ligands can regulate T cell survival and apoptosis, while also influencing the development and function of Tregs (not depicted), which have the potential to limit Type 2 activation to resolve inflammation [30].

Figure 3.. Notch can drive the differentiation and function of Type 2 innate effector cells in mice.

In the murine bone marrow (BM), Notch has a key role in steady-state hematopoiesis and is required for the effective development of group 2 innate lymphoid cells (ILC2s) from common-lymphoid progenitors (CLPs) and mast cell development from granulocyte-macrophage precursors (GMPs). In the murine lung, the infiltration of ILC2s during N. brasiliensis infection requires Notch. Notch signaling also drives recruitment of IL-25-responsive KLRG1⁺ (not depicted) inflammatory ILC2s (iILC2s) during allergic inflammation in the lung. Activation of Notch in natural, lung resident ILC2s (nILC2s) in vitro can induce functional plasticity, normally characteristic of iILC2s, including Rorc expression and co-production of IL-13/IL-17 [28]. Eosinophil accumulation in allergic inflammation may also depend on Notch signaling. In the intestine, Notch is a driver of effective granulocyte localization, key to helminth clearance. Notch signaling in mast cells helps to position them within the small intestinal epithelium. Loss of functional Notch signaling in basophils reduces the proportion of basophils in the lamina propria (LP). This diminishes the likelihood that they are in close proximity to CD4⁺ T cells at this site, associated with a reduction in the frequencies of Gata3⁺ Th2 cells in the cecum during T. muris infection [10]. In vitro studies of mast cells and basophils also suggest that Notch can facilitate optimal production of effector cytokines, including IL-4, IL-6 and IL-13 [10,67,68]. The role of Notch for the development and function of alternatively-activated macrophages remains to be determined (not depicted).