Vagal sensory neurons drive mucous cell metaplasia

Abstract

Airway sensory neuron-produced Substance P heightens allergy-induced goblet cell hyperplasia and hypersecretion of Muc5AC, electrically silencing these overreactive neurons reduced these components of lung type 2 allergic inflammatory response.

Figure 1.. Airway sensory neuron neurons reverse mucus metaplasia and mucin imbalance.

Optogenetic-stimulation of TRPV1^cre/wt∷ChR2^fl/wt and Tac1^cre/wt∷ChR2^fl/wt mice vagal sensory neurons increases BALF CD45⁺ cells (A), lung mucus deposition (B), and BALF Muc5AC/Muc5B ratio (C). In naïve C57BL6 mice, an acute capsaicin challenge (1 uM, i.n.) increased BALF levels of Muc5AC/Muc5B. Similar findings were observed in Rag1^−/− mice, suggesting that these effects are independent of B or T cells. These consequences were absent when mice were co-treated with QX-314 (100 μM, intranasal, D) to silence sensory neurons. Allergen-challenges increased airway mucus deposition (E) as well as in situ expression of Muc5AC/Muc5B (F), effects that were reversed by sensory neuron silencing using QX-314 (100 uM, aerosolized). QX-314 had no detectable outcomes when given to naïve mice (E–F). Muc5AC (red) and Muc5B (green) transcript expression (G–I) visualized by in situ-hybridization-stained sections of naïve (G) and OVA-exposed (H, I) lungs treated with saline (G, I) or QX-314 (100 μM; H). Scale 100 μm. Mucus deposition (purple; J–L) in Periodic acid–Schiff-stained sections of naïve (J) and OVA-exposed (K, L) lungs treated with saline (J, K) or QX-314 (100 μM; L). DAPI-stained cell nucleus (blue; G–I). Scale 100 μm. Mean ± S.E.M; Two-tailed unpaired Student’s t-test.

Figure 2:. Allergic inflammation-mediated goblet cell hyperplasia and mucin imbalance are controlled by SP release from vagal sensory neurons.

Goblet cell hyperplasia (blue; A–F) detected in Alcian Blue (AB)-stained sections of naïve (A) and OVA-exposed (B–F) lungs from littermate control (A–C), Tac1^−/− (D), or sensory neuron ablated mice (E, F) treated with vehicle (A, B, D, E), QX-314 (100 uM; C) or [Sar⁹, Met(O2)¹¹]-SP (F). Scale 100 μm. Littermate control mice challenged with OVA present a significant goblet cell hyperplasia (G), mucus metaplasia (H), BALF Muc5AC/Muc5B levels (I) as well as in situ expression of Muc5AC (J) relative to naïve mice. These effects were absent in sensory neuron silenced (G), ablated (G–I) or Tac1 knockout (G–I) mice, but partially rescued by daily intranasal administration of the stable substance P analog Sar⁹-Met-(O2)¹¹]-SP (G–I). Mean ± S.E.M; Two-tailed unpaired Student’s t-test.