Sulfated hyaluronan attenuates inflammatory signaling pathways in macrophages involving induction of antioxidants.
It is well recognized that high molecular weight hyaluronan (H-HA) exerts potent anti-inflammatory effects while its fragmentation into low molecular weight HA (L-HA) is discussed to promote inflammation. Chemical modification of HA with sulfate groups has been shown to foster its anti-inflammatory activity which seems to be maintained in sulfated low molecular weight HA derivatives (sL-HA). However, the molecular mechanisms by which sL-HA produces its anti-inflammatory activity are not understood. In this study, we used global quantitative proteomics combined with targeted analysis of key proteins to characterize the effect of sL-HA on fully differentiated human inflammatory macrophages (iMФ). Culture of iMФ with sL-HA did not affect cell viability but resulted in a reduced pro-inflammatory cytokine response of iMФ after activation indicating a profound counter-regulation of their initial inflammatory phenotype. Rapid internalization of sL-HA involving CD44 and scavenger receptors was observed. Furthermore, an upregulation of the antioxidants SOD2 and SOD3 was found while no oxidative stress was induced. Consequently, activity of transcription factors for inflammatory gene expression was downregulated in iMФ with sL-HA after activation whereas anti-inflammatory proteins were induced. This study proves anti-inflammatory properties of sL-HA and provides information on its regulatory mode of action on iMФ.
Department of Molecular Systems Biology, UFZ, Helmholtz-Centre for Environmental Research, Leipzig, Germany.
Florent
F
Jouy
Department of Dermatology, Venerology and Allergology, Leipzig University, Leipzig, Germany.
Nadine
N
Lohmann
Department of Dermatology, Venerology and Allergology, Leipzig University, Leipzig, Germany.
Elke
E
Wandel
Structural Bioinformatics, BIOTEC TU Dresden, Dresden, Germany.
Gloria
G
Ruiz-Gómez
Structural Bioinformatics, BIOTEC TU Dresden, Dresden, Germany.
M Teresa
MT
Pisabarro
Department of Biochemistry and Bioorganic Chemistry, Leipzig, Germany.
Annette G
AG
Beck-Sickinger
Biomaterials Department, INNOVENT e. V., Jena, Germany.
Matthias
M
Schnabelrauch
Biomaterials Department, INNOVENT e. V., Jena, Germany.
Stephanie
S
Möller
Department of Dermatology, Venerology and Allergology, Leipzig University, Leipzig, Germany.
Jan C
JC
Simon
Department of Molecular Systems Biology, UFZ, Helmholtz-Centre for Environmental Research, Leipzig, Germany.|Department of Bioanalytics, University of Applied Sciences and Arts of Coburg, Coburg, Germany.
Stefan
S
Kalkhof
Department of Molecular Systems Biology, UFZ, Helmholtz-Centre for Environmental Research, Leipzig, Germany.|Department of Chemistry and Bioscience, Aalborg University, Aalborg, Denmark.|Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, University of Leipzig, Leipzig, Germany.
Martin
M
von Bergen
Department of Dermatology, Venerology and Allergology, Leipzig University, Leipzig, Germany.
Sandra
S
Franz
Anti-inflammation; Antioxidants; Glycosaminoglycans; Macrophages; Sulfated hyaluronan