Maintenance of organismal health and survival requires integrated multi-cellular networks that sense and resist harmful threats. The immune and nervous systems are the two major sentinel interfaces that can detect external or internal perturbations, integrate perceived signals, and ultimately mount a unified response in attempt to maintain homeostasis. Injurious stimuli lead to inflammation, which involves activation of the immune, vascular, somatosensory, and autonomic systems to result in its cardinal signs: redness, swelling, pain, and heat [1]. Over a century ago, the observation that electrical stimulation of dorsal roots results in skin vasodilation sparked the emergence of the concept of “neurogenic inflammation” [2]. Neurogenic inflammation is a form of inflammatory response initiated by nerve activation and the subsequent release of neuropeptides, resulting in vasodilation, plasma extravasation, and edema [1], [2]. While neurogenic inflammation was once thought to be primarily driven by the activation of nervous system and largely independent of the immune system, it has become clear that these two systems interact extensively to fully execute their functions. The modes of communication between immune cells and neurons may rely on direct cell contacts, but perhaps more significantly on soluble mediators such as cytokines, chemokines, neuropeptides, and neurotransmitters [3]. Certain parallels are evident between the immune and nervous systems – both are abundantly distributed at the barrier surfaces, both are molecularly specialized to detecting danger signals, and both have the capacity to recall previous encounters and elicit memory responses [4].

One fundamental question is why we require two principal systems, namely the immune and nervous systems, to sense threats? While both the immune and nervous systems are individually capable of detecting threats, a dual-system involving bidirectional neuroimmune interactions may be better equipped to integrate situational cues and facilitate the initiation of a context-appropriate protective response [5]. For example, effective clearance of pathogens and toxins requires sustained immune protection through innate activation of antigen-specific adaptive immune responses. However, not all threats necessitate this. In the event of a sterile wound injury, an antigen-independent tissue repair response driven by innate immunity is generated instead of an antigen-specific adaptive immune response [6]. Growing evidence now underscores the critical roles of bidirectional neuroimmune communication in shaping responses that are specifically tailored to different threats or danger signals [7], [8], [9], [10], [11], [12]. In this review, we will discuss our current knowledge of neuroimmune circuits at barrier tissues, with a primary focus on skin biology in the context of wound healing, host defense against pathogens, as well as allergic inflammation and itch response. Where appropriate, we will compare and contrast these mechanisms in cutaneous tissue with those in other barrier surfaces, such as lung and gut.