UC San Diego

Group 2 Innate Lymphoid Cells (ILC2s) are newly discovered lymphocytes that play a vital role in helminth immunity and have been recently implicated in allergy. ILC2s produce type 2 cytokines IL-5 and IL-13, which orchestrate the development of mucus production, bronchoconstriction, and airway inflammation. Leukotriene C4 (LTC4) is a bioactive lipid and parent CysLT of LTD4 and LTE4. LTC4 and LTD4 are capable of binding to the ILC2 surface through CysLT1R and CysLT2R. Interleukin-33 (IL-33) is a cytokine secreted by bronchial epithelial cells that induces type 2 cytokines by group 2 innate lymphoid cells (ILC2s), resulting in many features present in asthma. Both CysLTs and airway epithelial derived cytokines are independently important in hypersensitivity diseases, including allergic asthma but few studies have investigated the effects of combinations of mediators. Our studies demonstrate that mice administered with both LTC4 and IL-33 have enhanced eosinophilia, airway inflammation, ILC2s, and type 2 cytokines compared with mice given IL-33 or LTC4 alone. Furthermore, RAG2-/- mice, which lack T and B lymphocytes but contain ILC2s exhibited ILC2 expansion and increased TH2 cytokine production in response to the combination of IL-33 and LTC4. IL-7R-/- mice, which lack all lymphocytes, were resistant to lung inflammation. Lastly, using CysLT1R-/- and CysLT2R-/- mice, we determined that LTC4 potentiated IL-33 induced airway inflammation and lung ILC2 regulation was dependent upon CysLT1R. New findings into mechanisms of ILC2 activation may lead to the discovery of novel treatments for asthma and other forms of allergic inflammatory diseases.