Soil-transmitted helminth parasites infect an estimated two billion people worldwide. Helminth-induced type 2 inflammation, which is characterized by the production of the cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13, promotes both acute host-protective immunity and chronic pathologic inflammation. Thus, there is an urgent need to better understand the regulation of protective versus pathologic type 2 inflammation to develop improved therapies to treat helminth infection and chronic inflammation. Group 2 innate lymphoid cells (ILC2s) are innate cells that produce type 2 cytokines that can mediate worm expulsion and contribute to chronic type 2 inflammation in the lung. However, how ILC2 responses are regulated to maintain a balance between helminth-induced protective versus pathologic type 2 inflammation remains unclear. Changes in smooth muscle contractility controlled by the sympathetic nervous system via the ?adrenergic receptor (?AR) and the accumulation and activation of immune cells in response to prostaglandins are also hallmarks of type 2 inflammation. The ?R and prostaglandin pathways have been targeted to treat asthma, allergies and chronic obstructive pulmonary disease (COPD) in patients, but whether these pathways regulate acute protective versus chronic pathologic ILC2 responses is unknown. Here, we demonstrate that human and murine ILC2s express the ?R and the prostaglandin D2 (PGD2) receptor CRTH2 (chemo-attractant receptor- homologous molecule expressed by Th2 cells). Additional preliminary data utilizing in vitro assays and in vivo approaches employing infection with Nippostrongylus brasiliensis, a rodent model for human hookworm infection, led to the central hypotheses that: (1) ?R is a direct negative regulator of acute protective ILC2 responses in the gut and (2) that the PGD2-CRTH2 pathway regulates ILC2 responses and promotes chronic pathologic type 2 inflammation in the lung. To directly test these hypotheses, we propose two Specific Aims.
In Specific Aim 1, we will test how the ?R pathway influences human and murine ILC2 phenotype and function in vitro and murine ILC2 responses in vivo during acute protective type 2 immunity to N. brasiliensis in the gut employing genetic and chemical manipulation of the ?R pathway, mutant mouse models and adoptive cell transfer approaches. Studies in Specific Aim 2 will test how the PGD2-CRTH2 pathway regulates human and murine ILC2 phenotype and function and murine ILC2 responses in vivo during chronic pathologic inflammation following N. brasiliensis infection employing cutting-edge bone marrow chimera and adoptive cell transfer approaches. Translational studies will focus on the phenotype and function of CRTH2- expressing ILC2s in the lung of human patients with severe chronic pulmonary inflammation in the context of COPD. We anticipate that a better understanding of the regulation of ILC2 responses during acute protective versus chronic pathologic type 2 cytokine-associated inflammation could lead to the development of new therapies that enhance anti-helminth immunity or limit pathologic inflammation.
Soil-transmitted helminth parasites infect approximately two billion people worldwide. Helminth-induced immune responses can mediate both protective immunity and chronic pathologic inflammation. This proposal aims to better understand how helminth-induced protective and pathologic immune responses are regulated.
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