Neuronal Guidance Proteins in the Fundamental Biology of Inflammation Resolution

The initiation and resolution of acute inflammatory responses rely on highly orchestrated biochemical and cellular programs, in which a finely tuned repertoire of mediators regulates the dynamics, migration, and effector functions of immune cells in space and time. Persistent, incompletely resolved inflammatory reactions disrupt this delicate homeostatic equilibrium and foster the development of severe acute and chronic diseases. Central mediators that terminate inflammatory responses and actively transition them into resolution are therefore of paramount importance. These include not only specialized pro-resolving lipid mediators but also peptide and protein mediators, cytokines with context-dependent pro-resolving function, stromal and neuronal signals, as well as cell-intrinsic resolution mechanisms such as efferocytosis, metabolic reprogramming, and tissue-repair programs. Innate and adaptive immune cells integrate these signals and, as major sources and effectors of pro-resolving mediators, drive clearance of harmful stimuli and dying cells and foster tissue repair. Within this broader network of pro-resolving pathways, neuronal guidance proteins (NGPs) are increasingly recognized as critical regulators of immune cell positioning and function that act far beyond their classical roles in axon guidance and are now regarded as integral components of the active inflammation-resolution program. This chapter interrogates the fundamental biology of selected NGPs-including Netrin-1, repulsive guidance molecule A (RGM-A), Semaphorin 7A (Sema7A), Neogenin (Neo1), and Plexin C1 (PLXC1)-and delineates their dual roles within inflammatory and resolution programs, with particular emphasis on how these cues sculpt leukocyte trafficking, promote cellular clearance, and drive immune cell reprogramming along the temporal axis from the early phase of acute inflammation to the restoration of tissue homeostasis.