Meta-inflammation through the lens of macrophage programming and nutrient-sensing ghrelin signaling

Macrophages are at the critical interface of immunity and metabolism. Metabolic reprogramming of macrophages, also known as meta-inflammation, has major implications in the pathogenesis of many chronic diseases. The infiltration and polarization of macrophages play critical roles in tissue homeostasis and inflammatory responses, thereby reshaping the tissue microenvironment. Macrophages have unique phenotypical and functional plasticity, making them attractive as therapeutic targets. Nutrient-sensing ghrelin is a gastrointestinal peptide hormone that functions through its receptor, growth hormone secretagogue receptor (GHSR), and is known to trigger hunger sensation, stimulate food intake, and promote fat deposition. Emerging evidence indicates that ghrelin/GHSR signaling is also a critical regulator of immunometabolism, modulating metabolic pathways in macrophages to enable their adaptation and functional responses to the tissue microenvironment. Here, we highlight the regulatory mechanisms of the ghrelin/GHSR system in macrophage reprogramming in meta-inflammation. In particular, we demonstrate the infiltration and differentiation of tissue-resident macrophages, and their functional impacts on the development and progression of metabolic and inflammatory dysfunctions. The dynamic and multifaceted roles of ghrelin/GHSR signaling in macrophage reprogramming could be leveraged to develop novel immunotherapies for meta-inflammatory conditions and diseases.