Galectin-3 interacts with PD-1 and counteracts the PD-1 pathway-driven regulation of T cell and osteoclast activity in Rheumatoid Arthritis

TY - JOUR

T1 - Galectin-3 interacts with PD-1 and counteracts the PD-1 pathway-driven regulation of T cell and osteoclast activity in Rheumatoid Arthritis

AU - Pedersen, Kathrine

AU - Nielsen, Morten Aagaard

AU - Juul-Madsen, Kristian

AU - Hvid, Malene

AU - Deleuran, Bent Winding

AU - Greisen, Stinne Ravn

PY - 2023/2

Y1 - 2023/2

N2 - Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation and bone erosions. The glycosylated programmed death-1 (PD-1) receptor plays an important role in regulating immune responses and maintaining tolerance. In this study, we focus on two features observed in RA: impairedPD-1 signalling and Galectin-3 (Gal-3) upregulation. We hypothesize that Gal-3binds PD-1 and PD-1 ligands, potentially contributing to impaired PD-1 signalling. PD-1 and Gal-3 levels in RA synovial fluid (SF) and plasma were evaluated by ELISA. PD-1 and Gal-3 interaction was examined by Surface PlasmonResonance and ELISA. PD-1, PD-L1 and Gal-3 expression on mononuclearcells from SF and peripheral blood as well as fibroblast-like synoviocytes wereexamined by flow cytometry. Effects of Gal-3 and PD-L1 on osteoclast formation was evaluated by tartrate-resistant acid phosphatase assay. We show thatGal-3 binds PD-1 and PD-L1. Results demonstrated high expression of PD-1and Gal-3 on mononuclear cells, especially from SF. Gal-3 inhibited PD-1 signalling when PD-L1 was present. Furthermore, a role of Gal-3 in osteoclastformation was observed in vitro, both directly but also through PD-1:PD-L1inhibition. Effects of Gal-3 on the PD-1 signalling axis are proposed to be inhibitory, meaning high Gal-3 levels in the complex synovial microenvironmentare not desirable in RA. Preventing Gal-3's inhibitory role on PD-1 signallingcould, therefore, be a therapeutic target in RA by affecting inflammatory T cellresponses and osteoclasts.

AB - Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation and bone erosions. The glycosylated programmed death-1 (PD-1) receptor plays an important role in regulating immune responses and maintaining tolerance. In this study, we focus on two features observed in RA: impairedPD-1 signalling and Galectin-3 (Gal-3) upregulation. We hypothesize that Gal-3binds PD-1 and PD-1 ligands, potentially contributing to impaired PD-1 signalling. PD-1 and Gal-3 levels in RA synovial fluid (SF) and plasma were evaluated by ELISA. PD-1 and Gal-3 interaction was examined by Surface PlasmonResonance and ELISA. PD-1, PD-L1 and Gal-3 expression on mononuclearcells from SF and peripheral blood as well as fibroblast-like synoviocytes wereexamined by flow cytometry. Effects of Gal-3 and PD-L1 on osteoclast formation was evaluated by tartrate-resistant acid phosphatase assay. We show thatGal-3 binds PD-1 and PD-L1. Results demonstrated high expression of PD-1and Gal-3 on mononuclear cells, especially from SF. Gal-3 inhibited PD-1 signalling when PD-L1 was present. Furthermore, a role of Gal-3 in osteoclastformation was observed in vitro, both directly but also through PD-1:PD-L1inhibition. Effects of Gal-3 on the PD-1 signalling axis are proposed to be inhibitory, meaning high Gal-3 levels in the complex synovial microenvironmentare not desirable in RA. Preventing Gal-3's inhibitory role on PD-1 signallingcould, therefore, be a therapeutic target in RA by affecting inflammatory T cellresponses and osteoclasts.

KW - Galectin-3

KW - PD-1

KW - autoimmunity

KW - co-inhibitory receptors

KW - inflammation

KW - rheumatoid arthritis

UR - http://www.scopus.com/inward/record.url?scp=85145415142&partnerID=8YFLogxK

U2 - 10.1111/sji.13245

DO - 10.1111/sji.13245

M3 - Journal article

C2 - 36537046

SN - 0300-9475

VL - 97

JO - Scandinavian Journal of Immunology

JF - Scandinavian Journal of Immunology

IS - 2

M1 - e13245

ER -