Polysialic Acid Restrains Inflammatory Monocyte Maturation

Ingredy Passos¹Benjamin Peschke²Shrey Gandhi³Judith Derdelinckx⁴Louisa Müller-Miny³Harald Neumann⁵Jan D Lünemann³Christian W Keller^6*

• ¹Universitatsklinikum Munster Klinik fur Neurologie mit Institut fur Translationale Neurologie, Münster, Germany
• ²Universitat Zurich Institut fur Experimentelle Immunologie, Zürich, Switzerland
• ³Universitat Munster, Münster, Germany
• ⁴Universitair Ziekenhuis Antwerpen, Edegem, Belgium
• ⁵Rheinische Friedrich-Wilhelms-Universitat Bonn Medizinische Fakultat, Bonn, Germany
• ⁶University of Freiburg Medical Center, Freiburg, Germany

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 development, resilience, and long-term integrity of the CNS. Here, we report that α2.8-linked low molecular weight polysialic acid (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 a pre-clinical animal model of multiple sclerosis (MS). Thus, by tuning myeloid cell phenotype in vivo, the therapeutic application of polysialic acid may offer a novel approach to target this cell population in the treatment of CNS autoimmunity.