TLR2 elicits IL-17-mediated RANKL expression, IL-17, and OPG production in neutrophils from arthritic mice.
We investigated the ability of neutrophils to express receptor activator of nuclear factor kappa-B ligand (RANKL), to secrete osteoprotegerin (OPG), and to produce IL-17. Arthritis was induced by intra-articular injection of zymosan, a ligand for Toll-like receptor 2 (TLR2). Frequencies of neutrophils in bone marrow (BM), blood and synovial fluid (SF), receptor expression, and cytokine production were evaluated by flow cytometry. 1A8 antibody (1A8 Ab) was used to deplete neutrophils in zymosan-injected SCID mice. IL-17, RANKL, and OPG amounts in SF, serum, or cell cultures were determined by ELISA. The development of arthritis was associated with increased secretion of IL-17, RANKL, and OPG in serum and SF, elevated frequencies of Ly6G(+)CD11b(+) cells in BM, blood, and SF and upregulated RANKL expression. Both IL-17 and OPG were absent in serum and SF after neutrophil depletion; therefore we assume that they were released by neutrophils. In vitro blood Ly6G(+)CD11b(+) cells from arthritic mice produced spontaneously IL-17, IFN-γ, and OPG and expressed RANKL. This phenotype was sustained by IL-17. TLR2 engagement increased IL-17 and IFN-γ production, potentiated IL-17-mediated RANKL expression, and inhibited OPG secretion. We conclude that TLR2 regulates the destructive potential of neutrophils and its targeting might limit joint alterations in arthritis.
Department of Immunology, Institute of Microbiology, Bulgarian Academy of Sciences, 26 Georgi Bonchev street, 1113 Sofia, Bulgaria.
Viktoriya
V
Milanova
Department of Immunology, Institute of Microbiology, Bulgarian Academy of Sciences, 26 Georgi Bonchev street, 1113 Sofia, Bulgaria.
Nina
N
Ivanovska
Department of Immunology, Institute of Microbiology, Bulgarian Academy of Sciences, 26 Georgi Bonchev street, 1113 Sofia, Bulgaria.
Petya
0000-0003-0920-3712
P
Dimitrova
D000818:Animals; D001168:Arthritis / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009504:Neutrophils / Q000378:metabolism*; D053244:Osteoprotegerin / Q000378:metabolism*; D010641:Phenotype; D053245:RANK Ligand / Q000378:metabolism*; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
D016207:Cytokines; C098680:Il17a protein, mouse; D020381:Interleukin-17; D053244:Osteoprotegerin; D053245:RANK Ligand; C493486:Tlr2 protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D051195:Toll-Like Receptor 2; D007371:Interferon-gamma