Host protective roles of type 2 immunity: parasite killing and tissue repair, flip sides of the same coin

Abstract

Metazoan parasites typically induce a type 2 immune response, characterized by T helper 2 (Th2) cells that produce the cytokines IL-4, IL-5 and IL-13 among others. The type 2 response is host protective, reducing the number of parasites either through direct killing in the tissues, or expulsion from the intestine. Type 2 immunity also protects the host against damage mediated by these large extracellular parasites as they migrate through the body. At the center of both the innate and adaptive type 2 immune response, is the IL-4Rα that mediates many of the key effector functions. Here we highlight the striking overlap between the molecules, cells and pathways that mediate both parasite control and tissue repair. We have proposed that adaptive Th2 immunity evolved out of our innate repair pathways to mediate both accelerated repair and parasite control in the face of continual assault from multicellular pathogens. Type 2 cytokines are involved in many aspects of mammalian physiology independent of helminth infection. Therefore understanding the evolutionary relationship between helminth killing and tissue repair should provide new insight into immune mechanisms of tissue protection in the face of physical injury.

Keywords: Eosinophils; Helminths; IL-4Rα; Macrophages; Th2 cells; Wound repair.

Fig. 1

Life cycle of N. brasiliensis in mice, demonstrating sites where tissue injury occurs. Stage 3 larvae (L3) infect the host by penetrating the skin resulting in local infiltration of host neutrophils and esoinophils. L3s enter blood vessels (∼6 h post-infection) and migrate to the lung bursting through capillaries (∼18–72 h) where, in the parenchyma, L3s mature to L4s. Damage caused by larval migration and neutrophilic inflammation leads to hemorrhage and acute lung injury. After approximately 48 h, larvae break through into the airways, are coughed up, swallowed and enter into the intestine where parasites mature and produce eggs (72 h). Adults that reside in the intestine cause local tissue damage and inflammation before being expelled in a highly Th2-dependent manner.

Fig. 2

Effector molecules involved in type 2 immune responses and host repair following N. brasiliensis infection. While the pathways involved in immune-mediated clearance and repair of tissue damage can be applied to infection of most helminths, the effector molecules depicted here apply specifically to infection with N. brasiliensis. As larvae pass through the lung, acute lung injury ensues following danger associated molecular patterns (DAMPs) and IL-1 secretion from airway epithelial cells, which in turn triggers IL-17 production and recruitment of neutrophils. Neutrophil influx in combination with mechanical damage from migrating larvae leads to injury and tissue hemorrhage. Concurrently, alarmins IL-33 and IL-25 are secreted from epithelial cells leading to recruitment and activation of both CD4+ T cells and innate lymphoid cells. Type 2 cytokines IL-4, 13, 9 and 5 increase in the tissue leading to eosinophilia, which in turn contributes to the pool of IL-4. Macrophages in the lung become alternatively activated by engagement of the IL-4Ra and secret factors such as RELMα, Ym1, arginase (Arg1) and insulin growth factor (IgF) that inhibit IL-17 production limiting further tissue damage. Additionally M2 macrophages simultaneously facilitate repair of the lung, along with eosinophils. Responses that occur in intestine follow a similar trend, although the damage from infection is not only initiated by parasite migration but also feeding on the intestine wall. Alarmins together with dendritic cells and mast cells stimulate a type 2 immune response resulting in alternative macrophage activation. AAMφ not only secrete mediators, like RELMα that help toward repair of the tissue and extracellular matrix remodeling, but are also involved in parasite killing following activation by parasite-specific antibodies secreted by B cells. Critically, epithelial cells and goblet cells play a key role in repair of tissue by generating factors like TGFβ, RELMα and RELMβ which contribute to extracellular matrix turnover. Approximately 1 week post infection with N. brasiliensis, the adult parasites are cleared from the intestine in a type 2 dependent manner involving IL-13-driven muscle contraction and increased mucus production in the epithelium. It is important to note that while TSLP effector function is redundant for host-protection against N. brasiliensis infection it is an important factor in other helminth models as discussed in Section 2.3.