Key Points

HRF secretion is enhanced by cytokines, HDM allergens, ATP, and adenosine.

Several HDM allergens enhance HRF secretion in a TLR2-dependent manner.

HRF elicits neutrophilic airway inflammation in HDM-sensitized mice.

Abstract

Histamine-releasing factor (HRF) is a multifunctional protein with fundamental intracellular functions controlling cell survival and proliferation. HRF is also secreted during allergic reactions and promotes IgE-mediated activation of mast cells and basophils. In this study, we investigated HRF secretion and its relevance to airway inflammation. HRF monomers were constitutively secreted from BEAS-2B human bronchial epithelial cells (HBECs) and converted to oligomers over the course of culture. Stimulation with house dust mite (HDM) extract increased HRF secretion substantially. Several cytokines involved in asthma pathogenesis showed moderate effects on HRF secretion but dramatically enhanced HDM-induced HRF secretion. HDM-induced HRF secretion from BEAS-2B cells and normal HBECs proceeded via TLR2. Consistent with this, multiple TLR2 ligands, including Der p 2, Der p 5, Der p 13, and Der p 21, induced HRF secretion. Der p 10 (tropomyosin) also promoted HRF secretion. Cell death or incubation with adenosine and ATP, compounds released upon cell death, also enhanced HRF secretion. Furthermore, intranasal administration of recombinant HRF elicited robust airway inflammation in HDM-sensitized mice in an FcεRI-dependent manner. Therefore, we conclude that HRF is a novel alarmin that promotes allergic airway inflammation.

Footnotes

This work was supported in part by the National Institutes of Health Grants AI146042 and AI153867.

K.K. performed most of the experiments. Y.K. performed some experiments. A.J. provided critical reagents. T.K. conceived and directed this study. T.K. wrote the manuscript, and all authors agreed on the final version of the manuscript.

The online version of this article contains supplemental material.

Abbreviations used in this article:

BALbronchoalveolar lavageBALFbronchoalveolar lavage fluidDAMPdamage-associated molecular patternDer pDermatophagoides pteronyssinusHBEChuman bronchial epithelial cellHDMhouse dust miteHMWhigh molecular weightHRFhistamine-releasing factorLJILa Jolla Institute for ImmunologysiRNAsmall interfering RNATSLPthymic stromal lymphopoietinWTwild typeReceived April 14, 2022.Accepted September 7, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.