AUTHOR=Passos Ingredy , Peschke Benjamin , Gandhi Shrey , Derdelinckx Judith , Müller-Miny Louisa , Neumann Harald , Lünemann Jan D. , Keller Christian W. 

TITLE=Polysialic acid restrains inflammatory monocyte maturation

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1656087

DOI=10.3389/fimmu.2025.1656087

ISSN=1664-3224

ABSTRACT=Sialic acids are widely distributed monosaccharides in the central nervous system (CNS), where they are predominantly found as terminal sialic acid residues, as well as in di-, oligo-, and polysialic forms on the glycocalyx, collectively contributing to the development, resilience, and long-term integrity of the CNS. Harnessing sialic acid–binding immunoglobulin-like lectin (Siglec) receptors by α2.8-linked polysialic acids has been shown to modulate immune responses. In this study, murine and human monocytes were exposed to α2.8-linked low molecular weight polysialic acid (α2.8-polySIA) in vitro, followed by phenotypic, functional, and transcriptomic analyses using flow cytometry and RNA sequencing; therapeutic efficacy was assessed in mice with experimental autoimmune encephalomyelitis (EAE), a pre-clinical model of multiple sclerosis (MS). Here, we report that α2.8-polySIA inhibits toll-like receptor-induced phenotypical and functional maturation of murine and human monocytes into pro-inflammatory effector cells equipped with operational antigen-presenting machinery. Moreover, RNA sequencing analyses revealed a shift towards a regulatory phenotype in human myeloid cells exposed to α2.8-polySIA. Finally, therapeutic treatment with α2.8-polySIA led to a milder disease course in EAE mice. Thus, by tuning myeloid cell phenotype in vivo, the therapeutic application of polysialic acid may offer a novel approach to modulate myeloid-driven inflammation in CNS autoimmunity.