Alginate microsphere compositions dictate different mechanisms of complement activation with consequences for cytokine release and leukocyte activation

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• 作者：Pontus Ø ; rning^a ; Kine Samset Hoem^a ; Abba Elizabeth Coron^a ; ^b ; Gudmund Skjå ; k-Bræ ; k^b ; Tom Eirik Mollnes^a ; ^c ; ^d ; Ole-Lars Brekke^d ; Terje Espevik^a ; Anne Mari Rokstad^a ; ^e ; ^{anne.m.rokstad@ntnu.no" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Alginate microcapsules ; Complement component 3 ; CR3 (CD11b/CD18) ; C5a ; Inflammation ; Polycation
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：10 May 2016
• 年：2016
• 卷：229
• 期：Complete
• 页码：58-69
• 全文大小：1689 K

文摘

The inflammatory potential of 12 types of alginate-based microspheres was assessed in a human whole blood model. The inflammatory potential could be categorized from low to high based on the four main alginate microsphere types; alginate microbeads, liquefied core poly-l-ornithine (PLO)-containing microcapsules, liquefied core poly-l-lysine (PLL)-containing microcapsules, and solid core PLL-containing microcapsules. No complement or inflammatory cytokine activation was detected for the Ca/Ba alginate microbeads. Liquefied core PLO- and PLL-containing microcapsules induced significant fluid phase complement activation (TCC), but with low complement surface deposition (anti-C3c), and a low proinflammatory cytokine secretion, with exception of an elevated MCP-1(CCL2) secretion. The solid core PLL-containing microcapsules generated lower TCC but a marked complement surface deposition and significant induction of the proinflammatory cytokines interleukin (IL-1)β, TNF, IL-6, the chemokines IL-8 (CXCL8), and MIP-1α (CCL3) and MCP-1(CCL2). Inhibition with compstatin (C3 inhibitor) completely abolished complement surface deposition, leukocyte adhesion and the proinflammatory cytokines. The C5 inhibitions partly lead to a reduction of the proinflammatory cytokines. The leukocyte adhesion was abolished by inhibitory antibodies against CD18 and partly reduced by CD11b, but not by CD11c. Anti-CD18 significantly reduced the (IL-1)β, TNF, IL-6 and MIP-1α and anti-CD11b significantly reduced the IL-6 and VEGF secretion. MCP-1 was strongly activated by anti-CD18 and anti-CD11b. In conclusion the initial proinflammatory cytokine responses are driven by the microspheres potential to trigger complement C3 (C3b/iC3b) deposition, leukocyte activation and binding through complement receptor CR3 (CD11b/CD18). MCP-1 is one exception dependent on the fluid phase complement activation mediated through CR3.