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Published on: February 6, 2020
Central role of complement membrane attack complex in monosodium urate crystal-induced neutrophilic rabbit knee
Nicole Tramontini1, Colleen Huber, Ru Liu-Bryan
1Pfizer Global Research and Development, Ann Arbor, Michigan, USA.
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.
Conclusion:
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.
Insights
The membrane attack complex (MAC) significantly reduces swelling and neutrophil infiltration in experimental gout. C6 and MAC activation are key drivers of gouty arthritis inflammation.
Area of Science:
- Immunology
- Rheumatology
- Complement System Biology
Background:
- Monosodium urate (MSU) crystals trigger gout inflammation primarily through neutrophil recruitment and activation.
- Interleukin-8 (IL-8) is a key chemokine in gout, but the role of complement system components, specifically the membrane attack complex (MAC), remains unclear.
- MSU crystals activate both classical and alternative complement pathways and directly cleave C5.
Purpose of the Study:
- To investigate the role of MAC, specifically the C6 component, in mediating urate crystal-induced arthritis.
- To determine if MAC activation contributes to IL-8 generation and neutrophil recruitment in experimental gout.
Main Methods:
- Intra-articular injection of MSU crystals into C6-deficient and C6-sufficient rabbits.
- Analysis of IL-8 levels, leukocyte influx (neutrophils and monocytes), and joint inflammation 24 hours post-injection.
Main Results:
- C6-deficient rabbits showed a significant (>60%) reduction in knee swelling compared to controls.
- MSU crystal-induced joint effusions in C6-deficient rabbits had lower IL-8 levels and fewer neutrophils.
- While mononuclear cells infiltrated all joints, substantial neutrophil infiltration was only observed in C6-sufficient rabbits.
Conclusions:
- MAC activation plays a significant role in intra-articular IL-8 production and neutrophil recruitment during experimental gouty arthritis.
- C6 and MAC activation represent potential therapeutic targets for managing neutrophil-driven joint inflammation in gout.
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