Differential Regulation of Allergic Airway Inflammation by Acetylcholine

Abstract

Acetylcholine (ACh) from neuronal and non-neuronal sources plays an important role in the regulation of immune responses and is associated with the development of several disease pathologies. We have previously demonstrated that group 2 innate lymphoid cell (ILC2)-derived ACh is required for optimal type 2 responses to parasitic infection and therefore sought to determine whether this also plays a role in allergic inflammation. RoraCre+ChatLoxP mice (in which ILC2s cannot synthesize ACh) were exposed to an allergenic extract of the fungus Alternaria alternata, and immune responses in the airways and lung tissues were analyzed. Airway neutrophilia and expression of the neutrophil chemoattractants CXCL1 and CXCL2 were enhanced 24 h after exposure, suggesting that ILC2-derived ACh plays a role in limiting excessive pulmonary neutrophilic inflammation. The effect of non-selective depletion of ACh was examined by intranasal administration of a stable parasite-secreted acetylcholinesterase. Depletion of airway ACh in this manner resulted in a more profound enhancement of neutrophilia and chemokine expression, suggesting multiple cellular sources for the release of ACh. In contrast, depletion of ACh inhibited Alternaria-induced activation of ILC2s, suppressing the expression of IL-5, IL-13, and subsequent eosinophilia. Depletion of ACh reduced macrophages with an alternatively activated M2 phenotype and an increase in M1 macrophage marker expression. These data suggest that ACh regulates allergic airway inflammation in several ways, enhancing ILC2-driven eosinophilia but suppressing neutrophilia through reduced chemokine expression.

Neural regulation of ILC2s in allergic airway inflammation

“…However, active AChE administration at baseline increased IL-5 and IL-13 levels from lung ILC2s, and M2 macrophage numbers. Overall, these results suggest that ACh suppresses airway neutrophilia by reducing CXCL1/CXCL2 levels and may play an in-direct role in negatively regulating ILC2-mediated allergic airway inflammation ( 16 ).…”

“…Importantly, the effects of ChAT deletion are ILC2 specific as the effector and proliferative capacities of lung CD4 + T cells which also produce ACh and express RORɑ ( 15 ) remained unaffected between the two genotypes ( 13 ). Conversely, Rora Cre+ ChAT LoxP mice intranasally challenged with AA extract exhibited more inflammatory M1 macrophages and neutrophil chemo-attractants CXCL1/CXCL2, while maintaining similar eosinophil, ILC2, and type 2 cytokine levels in the BAL fluid ( 16 ). These findings reveal that ChAT induced ACh production in ILC2s is critical for ILC2-mediated parasite clearance and prevention of airway neutrophilia.…”

The modulation of pulmonary group 2 innate lymphoid cell function in asthma: from inflammatory mediators to environmental and metabolic factors

“…Lung ILC2s express various subunits of both receptors 126 and can produce ACh in response to A. alternaria challenge or alarmins such as IL-33 and IL-25 126 , 127 . Although neither study examined the cholinergic role of ILC2s in allergic responses, a subsequent study revealed distinct effects of ACh during allergen-induced airway inflammation 128 . While ILC2-derived ACh limits neutrophilic inflammation by reducing the expression of the neutrophil chemoattractants CXCL1 and CXCL2, non-ILC2-derived ACh enhances ILC2-driven type 2 responses and subsequent eosinophilia 128 .…”

“…Although neither study examined the cholinergic role of ILC2s in allergic responses, a subsequent study revealed distinct effects of ACh during allergen-induced airway inflammation 128 . While ILC2-derived ACh limits neutrophilic inflammation by reducing the expression of the neutrophil chemoattractants CXCL1 and CXCL2, non-ILC2-derived ACh enhances ILC2-driven type 2 responses and subsequent eosinophilia 128 . In contrast, activation of the α7 nicotinic acetylcholine receptor (α7nAChR) by various agonists, such as nicotine and PNU-282987, mitigates ILC2-mediated AHR and airway inflammation in the A. alternaria model 129 , 130 .…”