摘要
The immune system is coordinated by an intricate network of stimulatory and inhibitory circuits that regulate host responses against endogenous and exogenous insults.Disruption of these safeguard and homeostatic mechanisms can lead to unpredictable inflammatory and autoimmune responses,whereas deficiency of immune stimulatory pathways may orchestrate immunosuppressive programs that contribute to perpetuate chronic infections,but also influence cancer development and progression.Glycans have emerged as essential components of homeostatic circuits,acting as fine-tuners of immunological responses and potential molecular targets for manipulation of immune tolerance and activation in a wide range of pathologic settings.Cell surface glycans,present in cells,tissues and the extracellular matrix,have been proposed to serve as“self-associated molecular patterns”that store structurally relevant biological data.The responsibility of deciphering this information relies on different families of glycan-binding proteins(including galectins,siglecs and C-type lectins)which,upon recognition of specific carbohydrate structures,can recalibrate the magnitude,nature and fate of immune responses.This process is tightly regulated by the diversity of glycan structures and the establishment of multivalent interactions on cell surface receptors and the extracellular matrix.Here we review the spatiotemporal regulation of selected glycan-modifying processes including mannosylation,complex N-glycan branching,core 2 O-glycan elongation,LacNAc extension,as well as terminal sialylation and fucosylation.Moreover,we illustrate examples that highlight the contribution of these processes to the control of immune responses and their integration with canonical tolerogenic pathways.Finally,we discuss the power of glycans and glycan-binding proteins as a source of immunomodulatory signals that could be leveraged for the treatment of autoimmune inflammation and chronic infection.
基金
supported by grants from SSP:co-funded by the European Union(ERC,GlycanSwitch,101071386).Views and opinions expressed are however those of the author(s)only and do not necessarily reflect those of the European Union or the European Research Council Executive Agency.Neither the European Union nor the granting authority can be held responsible for them.The work was also co-funded by EU GlycanTrigger-grant Agreement No:101093997.Views and opinions expressed are however those of the author(s)only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency.Neither the European Union nor the granting authority can be held responsible for them.SSP also acknowledges funding by“2022 LRA Lupus Innovation Award”and by“European Crohn’s and Colitis Organisation(ECCO)Pioneer Award 2021”.SSP also acknowledges the US Department of Defense,US Army Medical Research Acquisition Activity,FY18 Peer Reviewed Medical Research Program Investigator-Initiated Research Award(award number W81XWH1920053)as well as grant funded by the Portuguese Foundation for Science and Technology–FCT(EXPL/MED-ONC/0496/2021).IA acknowledges FCT for funding(2022.00337.CEECIND).JG acknowledges funding from ESCMID(ESCMID Research Grant 2022),ECCO(ECCO Grant 2023)and FCT(2020.00088.CEECIND).G.A.R acknowledges grants from the Argentinean Agency for Promotion of Science,Technology and Innovation(PICT 2017-0494,PICT-FBB 620 and PICT 2020-01552).The authors are also thankful for generous support from Sales(Argentina),Bunge&Born(Argentina),Baron(Argentina),Williams(Argentina)and Richard Lounsbery(USA)Foundations,as well as donations from Ferioli-Ostry and Caraballo families to GAR.
