Complement C5a potentiates uric acid crystal-induced IL-1β production

被引：60

作者：

An, Ling-Ling ^{[1
]}

Mehta, Payal ^{[1
]}

Xu, Linda ^{[2
]}

Turman, Sean ^{[1
]}

Reimer, Thornik ^{[1
]}

Naiman, Brian ^{[1
]}

Connor, Jane ^{[1
]}

Sanjuan, Miguel ^{[1
]}

Kolbeck, Roland ^{[1
]}

Fung, Michael ^{[1
]}

机构：

[1] MedImmune LLC, Dept Resp Inflammat & Autoimmune Dis, Gaithersburg, MD USA

[2] MedImmune LLC, Dept Antibody Discovery & Prot Engn, Gaithersburg, MD USA

来源：

EUROPEAN JOURNAL OF IMMUNOLOGY | 2014年 / 44卷 / 12期

关键词：

C5a; Gout; Inflammasome; IL-1; beta; monosodium urate/; uric acid (MSU) crystal; Priming; MEMBRANE ATTACK COMPLEX; NLRP3; INFLAMMASOME; ALTERNATIVE PATHWAY; GOUTY-ARTHRITIS; CUTTING EDGE; ACTIVATION; PHAGOCYTOSIS; RECEPTOR; INTERLEUKIN-1-BETA; RELEASE;

D O I：

10.1002/eji.201444560

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Anaphylatoxin C5a released upon complement activation is associated with both acute and chronic inflammations such as gout. The pathogenesis of gout was identified as uric acid crystal deposition in the joints that activates inflammasome, leading to IL-1 beta release. However, little is known about the interaction between complement activation and monosodium urate/uric acid (MSU) crystal-induced inflammasome activation or IL-1 beta production. Here, we report that MSU crystal-induced proinflammatory cytokines/chemokines in human whole blood is predominantly regulated by C5a through its interaction with C5a receptor. C5a induces pro-IL-1 beta and IL-1 beta production in human primary monocytes, and potentiates MSU or cholesterol crystals in IL-1 beta production. This potentiation is caspase-1 dependent and requires intracellular Ca2+ mobilization, K+ efflux, and cathepsin B activity. Our results provide insight into the role of C5a as an endogenous priming signal that is required for the initiation of uric acid crystal-induced IL-1 beta production. C5a could potentially be a therapeutic target together with IL-1 beta antagonists for the treatment of complement-dependent and inflammasome-associated diseases.

引用

页码：3669 / 3679

页数：11

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