Histamine-releasing factor (HRF) is a novel alarmin

Abstract Objective We are investigating how HRF secretion is regulated during allergic conditions. Results HRF interacts with a subset of IgE molecules. HRF dimer and oligomers, but not monomer, enhance the antigen sensitivity and magnitude of IgE-dependent mast cell activation. We found that BEAS-2B human bronchial epithelial cells constitutively secrete various forms of HRF (monomer, disulfide-linked dimer/oligomers). Secretion of these forms of HRF was enhanced by allergens such as house dust mites (HDM). HDM-mediated HRF secretion was dramatically enhanced by epithelial-derived cytokines (IL-25, IL-33, TSLP), Th2 cytokines (IL-4, IL-5, IL-13), and proinflammatory cytokines (IL-1b, IL-6, TNF), although the cytokines alone had much less effects. Mechanical injury of BEAS-2B cells and its byproducts (i.e., adenosine and ATP) also enhanced HRF secretion. In contrast, papain and bromelain (occupational allergens) as well as uric acid (NLRP3 inflammasome activator) exhibited limited effects on HRF secretion. Several high-molecular-weight forms (≥150 kDa) of HRF were found in body fluids. Interestingly, rhinovirus infection in humans and nasal instillation of HDM in mice, conditions predisposing asthma exacerbation, induced secretion of these HRF forms into airways. These results suggest that disulfide-linked HRF dimer/oligomers are involved in asthma exacerbation. Conclusion HRF dimer/oligomers secreted by epithelial and other cells enhance allergic inflammation as a novel alarmin.