The neuropeptide Y (NPY) gene appears to play an essential role in airway reactivity and may be a target for treating noneosinophilic asthma.
Higher expression of the NPY signaling molecule was seen in mice lacking Foxp1 and Foxp4 transcription factors. NPY induced noneosinophilic airway hyperreactivity by activating smooth muscle myosin light-chain phosphorylation, researchers reported in the Journal of Clinical Investigation.
Deleting the NPY gene in mice reduced airway hyperreactivity almost to normal levels, while incubating human lung tissue with recombinant NPY triggered bronchoconstriction, said Dr. Shanru Li and his associates at the University of Pennsylvania in Philadelphia. Future treatments for noneosinophilic asthma might target paracrine signaling from the airway epithelium to underlying smooth muscle.
The researchers also used transcriptome analysis to identify 10 genes that were significantly upregulated in the knockout mice and acted on airway smooth muscle cells to trigger airway hyperresponsiveness (AHR) in a paracrine manner. Among these, NPY was expressed at the highest levels, and deleting this gene in the Foxp1/Foxp4 knockout mice caused AHR to fall almost to normal levels. Incubating recombinant NPY with human and mouse lung tissue triggered marked bronchoconstriction in response to a methacholine challenge. Furthermore, phosphorylation of myosin light chain (pMLC), “a critical signaling event required for airway smooth muscle contraction,” increased with the methacholine challenge, but rose even more with concurrent exposure to NPY.
“Foxp1 and Foxp4 double mutants represent a model for noneosinophilic asthma, which remains poorly understood,” the researchers concluded. “The studies are among the first, to our knowledge, to mechanistically link a critical transcription pathway in airway epithelium that activates a paracrine response to the promotion of AHR in the absence of a Th2-induced eosinophilic inflammatory response.”
Most asthma therapies do not improve nonimmune asthma, which accounts for about half of asthma cases overall. While NPY gene variants have been linked to asthma, the specific molecular pathway was unknown, the researchers said. They found that Foxp1/4 knockout mice had greater airway smooth muscle contraction than control mice, especially after exposure to airway irritants. Notably, they did not find increased levels of the eosinophilic marker IL-13 or the neutrophilic inflammatory markers IL-17, IL-6, or keratinocyte-derived chemokine (KC) in airway epithelium from the knockout mice. “We did observe a modest increase in the numbers of neutrophils, but not macrophages, eosinophils, or lymphocytes in the bronchoalveolar lavage fluid in the Foxp1/4 knockout mutants,” they added (J Clin Invest. 2016 Apr. doi: 10.1172/JCI81389).
The National Institutes of Health funded the studies. The investigators had no disclosures.