Untangling Galectin-Driven Regulatory Circuits in Autoimmune Inflammation

Although progress has been made in understanding the mechanisms implicated in the pathogenesis of autoimmune inflammation, studies aimed at identifying the mediators of these pathways will be necessary to develop more selective therapies. Galectins, a family of glycan-binding proteins, play central roles in immune cell homeostasis. Whereas some members of this family trigger regulatory programs that promote resolution of inflammation, others contribute to perpetuate autoimmune processes. We discuss the roles of endogenous galectins and their specific glycosylated ligands in shaping autoimmune responses by fueling, extinguishing, or rewiring immune circuits. Understanding the relevance of galectin–glycan interactions in autoimmune inflammation could help to uncover novel pathways of tolerance breakdown, define molecular signatures for patient stratification and therapy responses, and open new avenues for immune intervention. Autoimmune diseases are heterogeneous dynamic conditions involving not only activation of autoreactive immune cells but also interruption of tolerogenic circuits. Biological agents have considerably improved therapeutic options for patients; however, current standard treatments solely reduce clinical symptoms and present severe side effects and variable response rates. Understanding the relevance of galectin-driven regulatory circuits and their alterations in autoimmune pathologies could pave the way for more rational tailored treatments. Galectins are endogenous lectins displaying specific, partially overlapping, and/or opposing functions in the regulation of immune cell programs; whereas some members of the galectin family (such as Gal1) mostly contribute to resolution of inflammatory responses, others (e.g., Gal3) can trigger proinflammatory signals or may even contribute to tissue repair.