NIH-Funded Scientists Discover Possible Genetic Tie to Asthma-Related Inflammation
Researchers at Harvard Medical School and University of California, Los Angeles, have discovered a possible connection between a gene linked to asthma and an immune mechanism for inflammation. The scientists found that in mice an aberrant gene causes immune cells that should mature into inflammation-reducing regulatory T cells to convert instead into inflammation-promoting Th17 cells. This imbalance worsens the airway inflammation that causes asthma symptoms. The findings indicate that therapies designed to interfere with this abnormal process may help reduce inflammation and control asthma symptoms. The study was funded by the National Institute of Allergy and Infectious Diseases with additional support from the National Heart, Lung and Blood Institute, both parts of the National Institutes of Health.
An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells
Mechanisms by which regulatory T (Treg) cells fail to control inflammation in asthma remain poorly understood. We show that a severe asthma-associated polymorphism in the gene encoding the interleukin (IL)-4 receptor alpha chain (Il4raR576) promotes conversion of induced Treg (iTreg) cells toward a T helper 17 (TH17) cell fate. This skewing is mediated by the recruitment by IL-4RαR576of the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which drives IL-17 expression by activating a pathway that involves extracellular-signal-regulated kinase, IL-6 and the transcription factor STAT3. Treg cell–specific deletion of genes that regulate TH17 cell differentiation, including Il6ra and RAR-related orphan receptor gamma (Rorc), but not of Il4 orIl13, prevented exacerbated airway inflammation in mice expressing Il4raR576 (hereafter referred to as Il4raR576 mice). Furthermore, treatment of Il4raR576 mice with a neutralizing IL-6-specific antibody prevented iTreg cell reprogramming into TH17-like cells and protected against severe airway inflammation. These findings identify a previously unknown mechanism for the development of mixed TH2–TH17 cell inflammation in genetically prone individuals and point to interventions that stabilize iTreg cells as potentially effective therapeutic strategies.
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