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Research Article: Polysialic acid restrains inflammatory monocyte maturation

Date Published: 2025-10-20

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 ?2.8-linked polysialic acids has been shown to modulate immune responses. In this study, murine and human monocytes were exposed to ?2.8-linked low molecular weight polysialic acid (?2.8-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 ?2.8-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 ?2.8-polySIA. Finally, therapeutic treatment with ?2.8-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.

Introduction:
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). Currently, available disease-modifying therapies, all of which have immunomodulatory and/or immunosuppressive properties, mainly improve the course of relapsing-remitting MS (RRMS), the most common disease phenotype. However, their effect on clinical disability progression is modest ( 1 , 2 ). In addition, currently approved therapies fail to show efficacy in the later secondary progressive phase,…

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