Communication is key: Innate immune cells regulate host protection to helminths

Abstract

Parasitic helminth infections remain a significant global health issue and are responsible for devastating morbidity and economic hardships. During infection, helminths migrate through different host organs, which results in substantial tissue damage and the release of diverse effector molecules by both hematopoietic and non-hematopoietic cells. Thus, host protective responses to helminths must initiate mechanisms that help to promote worm clearance while simultaneously mitigating tissue injury. The specialized immunity that promotes these responses is termed type 2 inflammation and is initiated by the recruitment and activation of hematopoietic stem/progenitor cells, mast cells, basophils, eosinophils, dendritic cells, neutrophils, macrophages, myeloid-derived suppressor cells, and group 2 innate lymphoid cells. Recent work has also revealed the importance of neuron-derived signals in regulating type 2 inflammation and antihelminth immunity. These studies suggest that multiple body systems coordinate to promote optimal outcomes post-infection. In this review, we will describe the innate immune events that direct the scope and intensity of antihelminth immunity. Further, we will highlight the recent progress made in our understanding of the neuro-immune interactions that regulate these pathways and discuss the conceptual advances they promote.

Keywords: antihelminth immunity; host protection; innate immune cells; innate immunity; neuro-immune crosstalk.

Figure 1

Overview of helminth-induced innate immune responses. Upon invasion, helminths cause substantial tissue damage as they burrow through various barriers and organs, such as the lungs, gut, and skin (1). Helminth also release excretory-secretory (ES) products that can act both locally and systemically (2). The damage-associated and helminth-derived signals promote the production of cytokine alarmins (IL-25, IL-33, and TSLP) from both hematopoietic and non-hematopoietic cells, such as macrophages (Macs) and epithelial cells (3). These early events drive the activation and expansion of innate immune cells, hematopoietic stem/progenitor (HSPCs), mast cells (MCs), basophils (Baso), dendritic cells (DCs), and ILC2s etc. (4). Moreover, innervating neurons can respond to helminth-derived signals by producing neuropeptides (NPs) and neurotransmitters (NTs) that directly influence immune cell activation and regulate inflammation (5). Collectively, these events induce the production of the type 2 cytokines IL-4, IL-5, and IL-13 that promote the polarization of type 2 T helper (T_H2), the induction of M2 macrophages and eosinophilia (6). Reviewed in (, , –43).

Figure 2

Neuro-Immune crosstalk regulates helminth-induced inflammation. In the context of helminth-induced inflammation, group 2 innate lymphoid cells (ILC2s) are activated by neuromedin U (NMU) that is released by choline acetyltransferase positive (ChAT⁺) neurons (185). Activated ILC2s also upregulate ChAT to promote acetylcholine biosynthesis, which serves to further amplify their production of type 2 cytokines (184). Helminth-activated ILC2s are also restricted by neuron-derived signals. Calcitonin gene-related peptide (CGRP), neuromedin B (NMB) and sympathetic neuron-derived norepinephrine (NE) inhibit ILC2 response in a manner that properly regulated helminth-induced inflammation (78, 182, 183).