Nociceptor inhibition as a new therapeutic approach for asthma

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When we hear somebody wheezing, coughing, showing chest tightness and shortness of breath, most of us will immediately recognize the underlying cause: Asthma. This is not a minor issue, but one affecting approximately 5% of the entire world population (and steeply growing every year) and causing the death of nearly 400000 people back in 2015 1. Furthermore, and besides the annoyance it creates to both children and adults, it represents a tremendous cost to public health systems, with an estimated expenditure of €1.15 billion per year in direct healthcare costs only within the UK 2.

Asthma is a chronic lung disease characterized by bronchial hyper-reactivity causing the inflammation of airways and tightening of the muscles surrounding them, leading to limited air flow as a consequence of narrower airways . It is caused by both environmental (e.g. contact with allergens or air pollutants) and genetic factors, as shown by genome-wide association studies (GWAS) linking genes encoding for proteins involved in innate immune response pathways -such as Interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP)- with the disease 3.

Physiologically, immune cells orchestrate the pathological airway response, being dendritic cells (DC), innate lymphoid type 2 cells (ILC2), differentiated T helper 2 cells (Th2) and eosinophils key players. The presence of allergens on the airways activate both epithelial and DC triggering a cascade of regulatory events mediated by cytokine secretion* that results in type 2 allergic airway inflammation and the aforementioned bronchial hyperresponsiveness (Figure 1).

Besides the immune response, there is also a neuronal response mediated by nociceptors that densely innervate airways. These nociceptors are physiologically important as they detect and respond to chemical and physical stimuli, initiating protective responses if needed, such as coughing. Thus, there is an important interplay between the immune and peripheral nervous system on that tissue to ensure the well-being of the organism. Now going back to asthma, it is known these patients have a denser network of nociceptors combined with a reduces activation threshold in response to allergens, which in practical terms means they generate a response more often than they should in the presence of even a small concentration of particles in the air and therefore the patient‘s symptoms can be prolonged and exasperating (or even life-threatening). Based on our previous knowledge about the role of nociceptors in pain (you can have a quick look to my posts about pain published in MI), we know the activation of nociceptors trigger the local release of neuropeptides such as substance P and calcitonin-gene related peptide (CGRP), increasing vascular permeability and stimulating vasodilation (neurogenic inflammation). So there is a contribution of nociceptors on the overall asthma process, implying they could be therapeutically targeted to alleviate the asthma symptoms. The problem is there is a big question mark about the molecular events happening between these two types of cells that concertedly intensify the process.

Once again, the group from Professor Clifford J. Woolf decided to explore the missing pieces in a recent paper published in Neuron 4, but first they had to confirm the involvement of nociceptors in asthma symptoms. To this end, allergic inflammation and bronchial hyperresponsiveness was induced in mice using ovalbumin as allergen (mice were sensitized to the egg protein previously). Then they tried three different approaches to substantiate their involvement:

1.- Activation of airway nociceptors using the TRPV1 agonist capsaicin administered intranasally (go to my previous posts for further insight) in both OVA treated and non-treated mice to then quantify the number of immune cells (looking to the biomarker CD45+). Allergic mice treated with capsaicin showed 6 times more immune cells than capsaicin-treated naïve ones. This result suggests that factors released by nociceptors in inflamed lung increases the recruitment of immune cells.

2.- Removal of airway nociceptors –using targeted diphtheria toxin-based cell ablation*- prevented the increase of immune cells in OVA-treated mice, compared to OVA-treated mice where nociceptors where not ablated.

3.- Co-application of the selective TRPV1 activator capsaicin (expressed in nociceptors) and the impermeable lidocaine derivative QX-314 -which can get through nociceptors via the pore of the activated TRPV1 and block action potential generation – to OVA-treated mice, reduced significantly the levels of CGRP and oedema compared to non-treated mice.

Once the association was stablished, they tried to modulate the severity of asthma by silencing airway nociceptors (the supposedly upstream modulator), either by removing them or by inhibiting them with QX-314. The result was a pronounced reduction of immune cells infiltration and bronchial responsiveness in a mice model having type 2 allergic airway inflammation (but not type 1 model). The main difference from these two is the subpopulation of CD4+ T cells involved in the immune response: Type 1 relies on T Helper 1 (TH1) cells and type 2 on TH2 cells. Depending on which type of cells gets activated, the secretion of inflammatory mediators will be different and so will be the signalling pathways activated. Thus, at best this would be a solution for certain subtypes of allergy, including the one mediated by TH2 cells.

Evaluation of the effect of QX-314 on the immune system showed that local exposure to up to 1 mM concentration had no effect over survival, chemotaxis or activation of macrophages and eosinophils in vitro -contrary to lidocaine- indicating that the supressing action of QX-314 over the immune system occurs through nociceptor inhibition.

A detailed dissection of the molecular signalling pathways involved in the activation of nociceptors during exposure to allergens followed, showing that interleukin 5 (IL-5) a type 2 effector cytokine secreted by several immune cells activates nociceptors, stimulating the secretion of neuropeptide vasoactive intestinal peptide (VIP), which in turn activates ILC2 (a type of innate lymphoid cells) and CD4+ (a subtype of T lymphocites expressing the CD4 glycoprotein) cells. Interestingly, these cells also produce IL-5 further activating nociceptors, which means a positive feedforward loop is created (Figure 1). This sequence of molecule and cell activation events leading to the production of pro-inflammatory cytokines, have an important contribution on the physiopathology of asthma, as shown by the alleviation of symptoms upon nociceptor inhibition. That means an entirely new therapeutic approach can be explored and could translate into an amelioration of the asthma-related symptoms to patients showing the specific type 2 inflammation activation profile.

References

  1. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016 Oct 8;388(10053):1459-1544. doi: 10.1016/S0140-6736(16)31012-1.
  2. Mukherjee M, et al. Estimating the incidence, prevalence and true cost of asthma in the UK: secondary analysis of national stand-alone and linked databases in England, Northern Ireland, Scotland and Wales-a study protocol. BMJ Open. 2014 Nov 4;4(11):e006647. doi: 10.1136/bmjopen-2014-006647.
  3. Ober C, Yao TC. The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev. 2011 Jul;242(1):10-30. doi: 10.1111/j.1600-065X.2011.01029.x. Review.
  4. Talbot S, Abdulnour RE, Burkett PR, Lee S, Cronin SJ, Pascal MA, Laedermann C, Foster SL, Tran JV, Lai N, Chiu IM, Ghasemlou N, DiBiase M, Roberson D, Von Hehn C, Agac B, Haworth O, Seki H, Penninger JM, Kuchroo VK, Bean BP, Levy BD, Woolf CJ. Silencing Nociceptor Neurons Reduces Allergic Airway Inflammation. Neuron. 2015 Jul 15;87(2):341-54. doi: 10.1016/j.neuron.2015.06.007.

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