Dopamine as a Potential Modulator of ILC2‐Driven Lung Inflammation via Mitochondrial Regulation

The connection between neuronal signaling and immune modulation has gained increasing attention in recent years, particularly in the context of allergic airway diseases [1]. Despite this progress, the precise mechanisms by which neurotransmitters like dopamine influence immune responses remain incompletely understood. Dopamine's established role in neurophysiological functions such as reward processing and motor control is now expanding into immunological domains, offering new insights into conditions like asthma [2]. In their recent study, Cao et al. investigate dopamine's impact on group 2 innate lymphoid cells (ILC2s), which are key mediators of type 2 inflammation, a form of immune response characterized by eosinophilic infiltration, elevated levels of cytokines like IL-4, IL-5, and IL-13, and heightened mucus production. This type of inflammation is commonly associated with allergic conditions such as asthma and atopic dermatitis. Using a combination of clinical observations and experimental models, the authors identify dopamine as a suppressor of ILC2-driven inflammation [3]. By acting on the dopamine receptor D1 (DRD1), dopamine inhibits mitochondrial oxidative phosphorylation (OXPHOS) in ILC2s, effectively dampening their production of pro-inflammatory cytokines IL-5 and IL-13 (Figure 1). This pathway provides an intriguing example of how neuronal signals can regulate immune responses and maintain a balanced pulmonary environment, ensuring that immune activity does not compromise respiratory function. The study seeks to establish a clinical link between plasma dopamine levels and asthma [3]. It found that plasma dopamine concentrations inversely correlate with circulating ILC2 numbers, and potentially also with pulmonary function in patients with asthma. Cao et al. used animal models to mechanistically investigate these observations. The administration of dopamine suppressed ILC2 proliferation, cytokine production, and airway inflammation in a DRD1-dependent manner. Conversely, genetic deletion of DRD1 enhanced ILC2 activity and worsened allergic responses, reinforcing dopamine's role as an inhibitory regulator. At the molecular level, transcriptomic and metabolic analyses revealed that dopamine impaired OXPHOS activity in ILC2s, reducing their energy supply and inflammatory capacity. Importantly, this suppression was reversible with the use of oltipraz, a compound that enhances mitochondrial function [3]. While the study marks a significant advancement in understanding dopamine's immunoregulatory functions, it also invites comparisons with other research in neuroimmune interactions. For example, previous research has examined the sympathetic nervous system's involvement in asthma, identifying β2-adrenergic receptor (β2AR) signaling as an inhibitory pathway for ILC2 activity. Notably, Moriyama et al. showed that β2AR agonists suppress ILC2-driven type 2 inflammation by reducing cytokine production, a mechanism that bears a striking resemblance to the effects observed with dopamine [4]. Apart from these promising findings, the study also highlights several critical questions about the regulation of type 2 inflammation. Among the most intriguing is the mechanism responsible for the depletion of dopaminergic neurons during allergic inflammation. The authors propose that inflammatory mediators such as IL-33 might contribute to this neuronal depletion, but the precise cellular and molecular processes remain unclear [3]. Additionally, the study focuses primarily on ILC2s, leaving open the possibility that dopamine may also influence other immune cells in the lungs, such as eosinophils or T cells [3]. In that regard, Wang et al. hinted at the possibility of dopamine acting as an inducer of type2 inflammation via DRD4-signaling in the lung [5]. This stimulating effect appeared to be age-related, with inflammation, airway hyperresponsiveness, and mucus overproduction affecting mainly neonate mice [5]. These contradicting findings emphasize the complexity of dopaminergic regulation of type 2 inflammation, which could potentially be age-dependent and associated with a balance between DRD1 and DRD4-receptor signaling. Although the findings provide compelling evidence for dopamine's immunomodulatory role, certain limitations should be acknowledged. First, the study is largely based on preclinical models, and its translational relevance to human asthma remains to be fully validated. Second, the interplay between DRD1 and other dopamine receptors in the broader immune landscape requires further investigation. Additionally, potential confounding factors, such as environmental influences on dopamine metabolism, were not extensively explored. The implications of this research extend beyond asthma, as type 2 inflammation is a key factor in several other chronic conditions. Notably, in atopic dermatitis, emerging evidence suggests that neuroimmune interactions involving dopamine could play a significant role [6]. By elucidating a neuroimmune circuit that regulates inflammation, Cao et al. provide a framework for studying other diseases characterized by dysregulated immunity, such as autoimmune disorders or chronic infections. Furthermore, the identification of dopamine as a potential therapeutic agent underscores the importance of exploring non-traditional pathways in drug development. In summary, this study sheds light on the complex interplay between the nervous and immune systems in allergic airway inflammation. Dopamine's ability to inhibit ILC2 responses through DRD1-mediated pathways represents a significant step forward in understanding asthma pathophysiology. It also highlights the potential of targeting neuroimmune interactions as a novel therapeutic strategy. Additionally, this new interplay of molecules could also be an answer to the innate mechanisms that govern local allergic rhinitis [7]. Future research should aim to validate these findings in diverse populations and uncover additional mechanisms linking neuronal and immune health. The authors declare no conflicts of interest. The data supporting the findings of this study are publicly available. They can be accessed through the DOI provided in the references.