A new approach to treat asthma: Silencing nociceptor neurons in the lungs
Article Jul 23, 2015
Asthma sufferers regularly experience coughing, wheezing, chest tightness, and shortness of breath. It is a disease that targets the airways of the lung, and affects almost 1 in 10 people. The lung contains sensory neurons called nociceptors that alert us to pain or irritation. Nociceptors respond to chemical, mechanical, or thermal stimuli, and activate coughing reflexes to protect our airways. Asthma sufferers tend to have denser nociceptor fibers1 which respond more quickly to irritants,2 suggesting that these cells would be useful targets for therapy.
In a study out this month in Neuron from the Woolf lab, investigators asked whether targeting these nociceptors, called Nav1.8+ sensory neurons, might affect inflammation in the lung. Nociceptors express transient receptor potential (TRP) channels. Chemical irritants activate TRPV1 and TRPA1 channels. When the authors used capsaicin to activate TRP channels on the nociceptors and induced an allergic response using the allergen ovalbumin, they found that immune cells were recruited in the lung. Ablating nociceptor neurons in a mouse model of asthma reduced inflammation of the airways after exposure to an allergen: fewer immune cells were recruited, suggesting that these neurons might be critical for immune activation in allergies and asthma.
When Talbot and colleagues silenced the nociceptor neurons with QX-314, a charged sodium channel inhibitor, prior to inflammatory challenge with ovalbumin, activation of the immune cascade and recruitment of immune cells was attenuated. They found that capsaicin, which activates TRP channels, induced the release of the neuropeptide VIP (vasoactive intestinal peptide). VIP release resulted in subsequent capillary leakiness. However, silencing of nociceptors using the sodium channel inhibitor prevented release of VIP and capillary leakiness. VIP release also led to the recruitment of immune cells such as CD4+ cells and resident innate lymphoid type two 2 cells, or ILC2 cells. But silencing of the nociceptors using QX-314 also prevented this immune cell recruitment.
The authors found that the effect of QX-314 was due in part to the cytokine IL-5. IL-5 is a major effector cytokine in asthma, and IL-5 levels were elevated in the mice after ovalbumin challenge. IL-5 induced release of VIP in nociceptors, and VIP release recruited CD4+ cells and ILC2 cells. However, blocked IL-5 increases after ovalbumin challenge. These results indicated that the sodium channel inhibitor could block cytokine activation of nociceptors in the lung, whose stimulation in turn can lead to inflammation and recruitment of immune cells in the presence of an allergen.
These findings have important implications for the future treatment of asthma and allergies that impact the lungs: drug therapies that target nociceptor activation in the lung, rather than targeting the immune system directly, may be effective to mitigate the inflammation and immune activation caused by allergens.
- Talbot S et al. (2015) Silencing Nociceptor Neurons Reduces Allergic Airway Inflammation. Neuron 87(2):341–354. doi: 10.1016/j.neuron.2015.06.007
- 1. Barnes PJ (1996) Neuroeffector mechanisms: the interface between inflammation and neuronal responses. J. Allergy Clin. Immunol. 98(5):73–81. doi: 10.1016/S0091-6749(96)70020-9
- 2. Canning BJ, Spina D (2009) Sensory Nerves and Airway Irritability. Handbook of Experimental Pharmacology 194:139-183. doi: 10.1007/978-3-540-79090-7_5
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