To the Editor Over the past few years, there has been an emerging interest in the role of the unfolded protein response (UPR) in respiratory disease. 1 Mammalian epithelial cells express a unique paralogue of the UPR sensor inositol-requiring enzyme (IRE) 1, IRE1β (encoded by the gene Ern2). Both IRE1α and IRE1β are endoplasmic reticulum (ER)-based endonucleases that generate the transcription factor X-box binding protein 1 (XBP1) s through splicing of Xbp1 mRNA. 2 In line with its tissue-specific expression, IRE1β has been implicated in mucin production in both lung and gut epithelia. 2 As mucus overproduction is an important clinical feature in many asthma patients, 3 IRE1β may pose an attractive pharmacological treatment option. In ovalbumin (OVA)-induced experimental asthma, IRE1β regulates mucin production through splicing of XBP14; however, its role in the more physiologically relevant house dust mite (HDM) model remains as yet unexplored.

We subjected IRE1β−/− mice and WT littermates to an acute HDM protocol to investigate the relevance of IRE1β as a major factor in asthma (Figure 1A). At time of sacrifice broncho-alveolar lavage fluid (BALF), tissues and mediastinal lymph nodes (MLN) were collected for analysis. Type 2 cytokine signaling by mediastinal lymph node cells was slightly increased in IRE1β−/− mice (Figure S1A), but no differences were observed in circulating antibodies (Figure S1B) or BALF immune cell infiltration (Figure S1D, gating strategy Figure S1C). These data show that IRE1β does not play a major role in the inflammatory response in asthma, confirming previous data. 4 To assess whether loss of IRE1β affects mucus production in the HDM model, we stained lung tissue sections of asthmatic mice using periodic acid-Schiff (PAS). Wild-type and IRE1β−/− mice exhibit similar percentages of PAS positive airway area, indicating that IRE1β does not drive mucus production during HDM-mediated asthma responses (Figure 1B). IRE1β has been suggested to act downstream of the Th2 cytokine IL-13 that is responsible for goblet cell metaplasia and mucus hypersecretion. 4 However, also when IRE1β−/− and WT littermates were challenged intratracheally with recombinant IL-13 (Figure 1C), no differences could be observed between the two genotypes (Figure 1D). These models indicate that IRE1β does not upregulate airway mucin production in these settings. Apart from mucin glycoprotein production, we studied the transcriptional responses in airways of treated mice to investigate the IRE1β-mediated mucin gene signature. As expected, both HDM and