Central role of complement membrane attack complex in monosodium urate crystal-induced neutrophilic rabbit knee synovitis.
OBJECTIVE
Monosodium urate monohydrate (MSU) crystals promote gouty inflammation that is critically mediated by neutrophil recruitment and activation. Interleukin-8 (IL-8) and closely related chemokines are major neutrophil chemotaxins in experimental gout. But MSU crystals also activate the classical and alternative pathways of complement, and MSU crystals directly cleave C5 on the crystal surface. Unlike IL-8, the roles in acute gout of individual complement-derived peptides and of the terminal C5b-9 complement components that comprise the membrane attack complex (MAC) are unclear. Hence, we studied rabbits deficient in the MAC component C6 to determine if MAC mediated urate crystal-induced arthritis.


METHODS
We injected C6-deficient and C6-sufficient rabbit knee joints with 10 mg of pyrogen-free urate crystals and analyzed IL-8 levels, leukocyte influx, and joint inflammation 24 hours later.


RESULTS
There was a significant decrease (>60%) in swelling in MSU crystal-injected knees of C6-deficient animals as compared with C6-sufficient animals (P < 0.05). An attenuated rise in MSU crystal-induced joint effusion levels of IL-8 also was observed, which was concordant with diminished numbers of neutrophils (P < 0.05) but not monocytes in MSU crystal-induced knee synovial fluid from C6-deficient animals. Synovial tissue analysis confirmed mononuclear leukocyte infiltration in response to MSU crystal injection in all animals, but substantial neutrophil infiltration only in C6-sufficient animals.


CONCLUSIONS
MAC activation appears to play a major role in intraarticular IL-8 generation and in neutrophil recruitment in experimental acute gouty arthritis of the rabbit knee. C6 and MAC activation may represent novel therapeutic targets for suppression of neutrophil-mediated joint inflammation in gout.
Tramontini
Nicole
N
Pfizer Global Research and Development, Ann Arbor, Michigan, USA.
Huber
Colleen
C
Liu-Bryan
Ru
R
Terkeltaub
Robert A
RA
Kilgore
Kenneth S
KS
D000818:Animals; D003183:Complement C6 / Q000502:physiology; D015938:Complement Membrane Attack Complex / Q000502:physiology*; D003460:Crystallization; D006073:Gout / Q000209:etiology*; D016209:Interleukin-8 / Q000032:analysis; D007719:Knee Joint; D009504:Neutrophils / Q000473:pathology; D011817:Rabbits; D013585:Synovitis / Q000139:chemically induced*; D014527:Uric Acid
D003183:Complement C6; D015938:Complement Membrane Attack Complex; D016209:Interleukin-8; D014527:Uric Acid