Myeloid-related proteins 8 and 14 contribute to monosodium urate monohydrate crystal-induced inflammation in gout.
OBJECTIVE
Monosodium urate monohydrate (MSU) crystal-induced interleukin-1β (IL-1β) secretion is a critical factor in the pathogenesis of gout. However, without costimulation by a proIL-1β-inducing factor, MSU crystals alone are insufficient to induce IL-1β secretion. The responsible costimulatory factors that act as a priming endogenous signal in vivo are not yet known. We undertook this study to analyze the costimulatory properties of myeloid-related protein 8 (MRP-8) and MRP-14 (endogenous Toll-like receptor 4 [TLR-4] agonists) in MSU crystal-induced IL-1β secretion and their relevance in gout.


METHODS
MRP-8/MRP-14 was measured in paired serum and synovial fluid samples by enzyme-linked immunosorbent assay (ELISA) and localized in synovial tissue from gout patients by immunohistochemistry. Serum levels were correlated with disease activity, and MSU crystal-induced release of MRPs from human phagocytes was measured. Costimulatory effects of MRP-8 and MRP-14 on MSU crystal-induced IL-1β secretion from phagocytes were analyzed in vitro by ELISA, Western blotting, and polymerase chain reaction. The impact of MRP was tested in vivo in a murine MSU crystal-induced peritonitis model.


RESULTS
MRP-8/MRP-14 levels were elevated in the synovium, tophi, and serum of patients with gout and correlated with disease activity. MRP-8/MRP-14 was released by MSU crystal-activated phagocytes and increased MSU crystal-induced IL-1β secretion in a TLR-4-dependent manner. Targeted deletion of MRP-14 in mice led to a moderately reduced response of MSU crystal-induced inflammation in vivo.


CONCLUSIONS
MRP-8 and MRP-14, which are highly expressed in gout, are enhancers of MSU crystal-induced IL-1β secretion in vitro and in vivo. These endogenous TLR-4 ligands released by activated phagocytes contribute to the maintenance of inflammation in gout.
University Hospital Muenster and University Children's Hospital Muenster, Muenster, Germany.
Dirk
D
Holzinger
Nadine
N
Nippe
Thomas
T
Vogl
Kristina
K
Marketon
Vijayashree
V
Mysore
Toni
T
Weinhage
Nicola
N
Dalbeth
Bregina
B
Pool
Tony
T
Merriman
Dominique
D
Baeten
Annette
A
Ives
Nathalie
N
Busso
Dirk
D
Foell
Sylvette
S
Bas
Cem
C
Gabay
Johannes
J
Roth
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D040501:Calgranulin A / Q000378:metabolism*; D040502:Calgranulin B / Q000378:metabolism*; D002478:Cells, Cultured; D003460:Crystallization; D004195:Disease Models, Animal; D005260:Female; D006073:Gout / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010586:Phagocytes / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism*
D040501:Calgranulin A; D040502:Calgranulin B; D053583:Interleukin-1beta; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014527:Uric Acid