Editors' ChoiceINNATE IMMUNITY

MID1 Mediates Acute Asthma Exacerbations

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Science Translational Medicine  30 Jan 2013:
Vol. 5, Issue 170, pp. 170ec22
DOI: 10.1126/scitranslmed.3005777

Asthma leaves its victims breathless—from young to old—and shows no signs of letting up. Asthma-related health care costs are rising, and in the United States, nine patients die each day from asthma. Rhinovirus (RV)–induced acute asthma exacerbations account for 60 to 80% of asthma attacks globally, a problem that remains without any current viable therapy. Scientists struggle to decipher asthma’s pathogenic mechanisms while continuing to search for new therapies.

Now, Collison et al. have identified a new protein that participates in the pathophysiology of asthma: the microtubule-associated E3 ubiquitin ligase midline 1 (MID1). This protein is important in embryonic development yet, surprisingly, may play a role in mediating asthma. Mutations in MID1 are associated with inherited malformations characterized by midline facial defects, such as cleft lip or cleft palate.

Because acute exacerbations of allergic asthma are frequently associated with RV infection, the authors used the house dust mite (HDM) and RV infection mouse models to assess the role of MID1 and innate immune pathways involved in asthma attacks.

The authors showed that after exposure to HDM or RV infection, MID1 is up-regulated in bronchial epithelium via Toll-like receptor 4 (TLR4) and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). The MID1 protein also decreases protein phosphatase 2A (PP2A) activity, an important enzyme that inhibits downstream proinflammatory transcription factors, including nuclear factor–κβ activity. The authors also found that inhibition of MID1 or agonist activation of PP2A in HDM-exposed mice reduced airway hyperreactivity (AHR) and allergic inflammation. Furthermore, MID1 inhibition limited RV-induced exacerbation of allergic inflammation and AHR. Going a step further, the authors showed that MID1 was up-regulated in primary human bronchial epithelial cells upon HDM and RV exposure, and that this up-regulation correlated with several markers of innate immune activation.

These findings are meaningful because they identify MID1 as an important player in allergic inflammation and innate immune pathway activation. From a clinical standpoint, this highlights a possible mechanism to explain RV-induced acute asthma exacerbations, for which MID1 may be a viable therapeutic target needing further study. If true, the translational impact of this work could be quite important.

It is tragic that patients, both young and old, continue to die every day from asthma. Because acute exacerbations are the conduit that can lead to asthma deaths, this discovery may be an exciting next chapter in asthma research.

A. Collison et al., The E3 ubiquitin ligase midline 1 promotes allergen and rhinovirus-induced asthma by inhibiting protein phosphatase 2A activity. Nat. Med., published online 20 January 2013 (10.1038/nm.3049). [Full text]

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