Targeting neuroimmune cross-talk in insulin resistance, energy homeostasis, and metabolic (dysfunction)-associated fatty liver disease (MAFLD)

Neuroimmune interactions are gaining attention for roles in development and progression of type-2 diabetes (T2D). Crosstalk between the immune system and components of the peripheral nervous system have been described in key metabolic tissues, including the liver and adipose tissue. In the liver, macrophages have been implicated in steatosis-induced neuropathy and systemic insulin resistance. In adipose tissue, macrophages physiologically control thermogenic capacity by regulating neurotransmitter release. A subset of macrophages that interacts with peripheral innervation has been characterized as nerve-associated macrophages (NAMs). Bona fide NAMs have been functionally and phenotypically characterized in adipose tissue and other peripheral tissues, but not in the liver. Sympathetic innervation in the liver undergoes dynamic and reversible remodeling with insulin resistance and hepatic steatosis, this remodeling has been associated with macrophage inflammatory signaling. The population dynamics and functional diversity of nerve-interacting macrophages in the liver remains unknown. Similarly, the dynamic changes in liver innervation across the whole spectrum of metabolic (dysfunction)-associated fatty liver disease (MAFLD) have not been characterized. This proposal addresses the following questions: How are liver NAMs phenotypically distinct from other liver macrophages? Do liver NAMs contribute to liver neuropathy in insulin resistance? And, do liver NAMs contribute to the resolution of MAFLD and restoration of systemic metabolic homeostasis? To address these questions, we will characterize neuroimmune interactions in MAFLD, ranging from simple steatosis to the fibroinflammatory stages of steatohepatitis. Through mechanistic murine modelling, cellular and molecular characterization and extensive use of public data repositories of human data, we will map macrophage-neuron interactions in MAFLD. We will develop novel candidate regulators of these interactions as future testable therapeutic targets.