First Responders: Innate Immunity to Helminths

Abstract

Helminth infections represent a significant public health concern resulting in devastating morbidity and economic consequences across the globe. Helminths migrate through mucosal sites causing tissue damage and the induction of type 2 immune responses. Antihelminth protection relies on the mobilization and activation of multiple immune cells, including type 2 innate lymphocytes (ILC2s), basophils, mast cells, macrophages, and hematopoietic stem/progenitor cells. Further, epithelial cells and neurons have been recognized as important regulators of type 2 immunity. Collectively, these pathways stimulate host-protective responses necessary for worm expulsion and the healing of affected tissues. In this review we focus on the innate immune pathways that regulate immunity to helminth parasites and describe how better understanding of these pathways may lead to the development of new therapeutic strategies.

Keywords: Mucosal Immunology; helminth parasites; innate immunity; type 2 cytokines.

Figure 1.. Initiation of anti-helminth responses at barrier surfaces.

Helminths affect barrier surfaces such as the lungs, gut and skin, causing tissue damage. In turn, epithelial cells release cytokine alarmins including IL-25, IL-33 and TSLP, which activate multiple innate immune cells including type 2 innate lymphoid cells (ILC2s), mast cells (MCs), basophils (Baso), γδ+ T cells, neutrophils (Neu) and dendritic cells (DCs). Further, cytokine alarmins induce the recruitment of hematopoietic stem/progenitor cells (HSPCs), such as type 2 multipotent progenitor cells (MPP^type2), that differentiate (dotted line) into innate immune cells and contribute to helminth-induced inflammation. In addition to epithelial cells, neurons have been recently shown to respond to helminth-derived products and initiate type 2 responses. Collectively these signals result in the secretion of type 2 cytokines including IL-4, IL-5 and IL-13. In turn, these cytokines promote host-protective responses such as the polarization of M2 macrophages (M2 mac) and the recruitment of eosinophils (Eos) resulting in the expulsion of the parasites and the healing of the affected tissues.

Figure 2.. Neuronal regulation of type 2 responses.

Novel studies have demonstrated that neuron-derived signals modulate type 2 responses. Neuronal expression of Neuromedin U has been shown to activate ILC2s and promote anti-helminth immunity. Conversely, β2-adrenergic receptor (β2AR) agonists were shown to inhibit ILC2 responses, suggesting that neuronderived epinephrine may regulate ILC2s. Collectively, these studies suggest that neurons may positively and negatively regulate ILC2 responses. However, whether neurons and other effector cell populations engage in crosstalk that is capable of influencing helminth-induced inflammation remains to be fully defined.

Figure 3.. Cooperative actions of innate cells activate M2 macrophages.

M2 macrophages can be induced by multiple mechanisms in the context of helminth infection. Type 2 cytokines, produced by ILC2s, basophils, mast cells, eosinophils and neutrophils contribute to M2 macrophage responses. Additionally, epithelial cells release adenosine in response to the helminth-induced damage, which further amplifies M2 macrophage activation. However, whether these signals differentially act on tissue-resident and monocyte-derived macrophages remains unknown. Further, whether neuronal-derived signals also regulate macrophage activation has not been determined.