<p>Persistent, unresolved inflammatory processes disrupt the complex homeostatic state and lead to severe disease, ultimately resulting in organ failure, shock, and death. The mediators that monitor and control the programmed mechanisms in tissue homeostasis and repair remain elusive. A recently discovered group of endogenous proteins, termed neuronal guidance proteins (NGPs), has gained attention as important mediators of immunoregulation and tissue homeostasis through their role in the complex interplay between metabolic reprogramming and immunity. In murine peritonitis, the deficiency of the NGP Plexin C1 (PLXC1^−/−) led to an increase in neutrophil and Ly6C^hi monocyte recruitment to the injury site and a decrease in the phagocytosis rate. This was accompanied by a decrease in the endogenous biosynthesis of specialized proresolving lipid mediators (SPMs) such as Maresin-1 and Protectin DX and finally by a lengthening of the resolution interval. Peritoneal macrophages (MΦs)^PLXC1−/− followed specific strategies to adapt their metabolism to catabolic conditions, by reducing fatty acid oxidation and oxidative phosphorylation, increasing aerobic glycolysis and activation of the pentose phosphate pathway, and disrupting the tricarboxylic acid cycle. The decreased MΦs^PLXC1−/− citrate levels corresponded with a lipid mediator profile in which PGD₂ and PGE₂ were greatly decreased in murine PLXC1^−/− peritoneal exudates, indicating a lesser effect on lipid mediator class switching and ultimately the formation of SPMs. Analysis of the related signaling networks indicated mTOR and AKT2 phosphorylation pathways are critical determinants of metabolic reprogramming in activated MΦs^PLXC1−/−. These findings highlight a novel role for PLXC1 in regulating the crosstalk between immunometabolism and inflammation resolution programs in severe inflammation.</p>