Background Sulfation of heparan sulfate proteoglycans (HSPGs) is critical for the binding and signaling of ligands that mediate inflammation. Extracellular 6-O-endosulfatases regulate posttranslational sulfation levels and patterns of HSPGs. In this study, extracellular 6-O-endosulfatases, sulfatase (Sulf)-1 and Sulf-2, were evaluated for their expression and function in inflammatory cells and tissues.
Methods Harvested human peripheral blood mononuclear cells were treated with phytohemagglutinin and lipopolysaccharide, and murine peritoneal macrophages were stimulated with interleukin (IL)-1β for the evaluation of Sulf-1 and Sulf-2 expression. Sulf expression in inflammatory cells was examined in the human rheumatoid arthritis (RA) synovium by immunofluorescence staining. The antigen presentation and phagocytic activities of macrophages were compared according to the expression state of Sulfs. Sulfs-knockdown macrophages and Sulfs-overexpressing macrophages were generated using small interfering RNAs and pcDNA3.1 plasmids for Sulf-1 and Sulf-2, respectively.
Results Lymphocytes and monocytes showed weak Sulf expression, which remained unaffected by IL-1β. However, peritoneal macrophages showed increased expression of Sulfs upon stimulation with IL-1β. In human RA synovium, two-colored double immunofluorescent staining of Sulfs and CD68 revealed active upregulation of Sulfs in macrophages of inflamed tissues, but not in lymphocytes of lymphoid follicles. Macrophages are professional antigen-presenting cells. The antigen presentation and phagocytic activities of macrophages were dependent on the level of Sulf expression, suppressed in Sulfs-knockdown macrophages, and enhanced in Sulfs-overexpressing macrophages.
Conclusion The results demonstrate that upregulation of Sulfs in macrophages occurs in response to inflammation, and Sulfs actively regulate the antigen presentation and phagocytic activities of macrophages as novel immune regulators.
Citations
Citations to this article as recorded by
6-O-endosulfatases in tumor metastasis: heparan sulfate proteoglycans modification and potential therapeutic targets Mengzhen Han American Journal of Cancer Research.2024; 14(2): 897. CrossRef
The prognostic value and immunological role of SULF2 in adrenocortical carcinoma Jiusong Yan, Xiaodu Xie, Qinke Li, Peihe Liang, Junyong Zhang, Guangyong Xu Heliyon.2023; 9(2): e13613. CrossRef
Machine learning-based metabolism-related genes signature, single-cell RNA sequencing, and experimental validation in hypersensitivity pneumonitis Jie He, Bo Wang, Meifeng Chen, Lingmeng Song, Hezhi Li Medicine.2023; 102(40): e34940. CrossRef
Extracellular sulfatase-2 is overexpressed in rheumatoid arthritis and mediates the TNF-α-induced inflammatory activation of synovial fibroblasts Ruby J. Siegel, Anil K. Singh, Paul M. Panipinto, Farheen S. Shaikh, Judy Vinh, Sang U. Han, H. Mark Kenney, Edward M. Schwarz, Cynthia S. Crowson, Sadik A. Khuder, Basil S. Khuder, David A. Fox, Salahuddin Ahmed Cellular & Molecular Immunology.2022; 19(10): 1185. CrossRef
Heparan Sulfate Glycosaminoglycan Is Predicted to Stabilize Inflammatory Infiltrate Formation and RANKL/OPG Ratio in Severe Periodontitis in Humans Roko Duplancic, Marija Roguljic, Darko Bozic, Darko Kero Bioengineering.2022; 9(10): 566. CrossRef
Mood Regulatory Actions of Active and Sham Nucleus Accumbens Deep Brain Stimulation in Antidepressant Resistant Rats Rajas P. Kale, Thanh Thanh L. Nguyen, J. Blair Price, Nathanael J. Yates, Ken Walder, Michael Berk, Roy V. Sillitoe, Abbas Z. Kouzani, Susannah J. Tye Frontiers in Human Neuroscience.2021;[Epub] CrossRef