Prostaglandin Regulation of Type 2 Inflammation

Principal Investigator: Elia Tait Wojno

Baker Institute for Animal Health
Sponsor: NIH-National Institute of Allergy and Infectious Diseases (NIAID)
Grant Number: 1K22AI116729-01A1
Title: Prostaglandin Regulation of Type 2 Inflammation
Project Amount: $160,400
Project Period: July 2016 to June 2017

DESCRIPTION (provided by applicant): 

This project investigates the regulation of innate immune responses in the lung during type 2 immune responses, which promote protective immunity to helminth parasites but can also cause chronic inflammation and pathology during helminth infection and allergy. My postdoctoral work, presented as preliminary data, demonstrates that group 2 innate lymphoid cells (ILC2s), a recently described innate immune cell type that promotes type 2 inflammation in the lung, respond to the bioactive lipid prostaglandin D2 (PGD2) via expression of the receptor CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells). I employ in vitro assays and in vivo infection with Nippostrongylus brasiliensis, a rodent model of hookworm infection and type 2 pulmonary inflammation, to show that type 2 inflammation in the lung in this model is dependent on CRTH2-expressing ILC2s. I also show that ILC2 responses to IL-33, a key cytokine that drives type 2 inflammation, are partially CRTH2-dependent. These data led to the central hypothesis that IL-33 induces PGD2 production that promotes CRTH2-expressing ILC2 responses during type 2 inflammation in the lung. To directly test this, I propose two Specific Aims. Aim 1 will examine mechanisms by which the PGD2-CRTH2 pathway influences ILC2 responses and helminth-induced type 2 inflammation in the lung, and Aim 2 will test how IL-33-dependent type 2 inflammation may be mediated through the PGD2-CRTH2 pathway, using cutting-edge approaches and complementary analyses of murine and human samples. Insights into how the PGD2-CRTH2 pathway regulates type 2 inflammation will inform the development and effective usage of therapies to treat type 2 inflammatory diseases. Critically, this research project will generate a rich data set that will become the foundation for future NIH funding applications.