Figure 1. Elements of the systemic and local cholinergic anti-inflammatory pathway proposed to augment cutaneous disease progression.

Stress can initiate a systemic response to activate the systemic cholinergic anti-inflammatory pathway through an efferent relay and stimulate acetylcholine (ACh) release from neuronal cells in the skin (e.g. nerve cells) to potentially act on keratinocytes. The non-neuronal cholinergic system in keratinocytes is capable of producing ACh that can be released into the extracellular space to activate nAChRs. Consequently, nAChR activation dampens AMP production and epidermal barrier integrity. Injury or infection during stress can either initiate or exacerbate existing skin pathologies. Episodes of more frequent or severe outbreaks of skin disease can signal a negative feedback loop back to the brain to provoke a secondary stress response to further suppress keratinocyte AMP and barrier function.