Complement factor B is the downstream effector of TLRs and plays an important role in a mouse model of severe sepsis

Lin Zou, Yan Feng, Yan Li, Ming Zhang, Chan Chen, Jiayan Cai, Yu Gong, Larry Wang, Joshua M. Thurman, Xiaobo Wu, John P. Atkinson, Wei Chao

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Severe sepsis involves massive activation of the innate immune system and leads to high mortality. Previous studies have demonstrated that various types of TLRs mediate a systemic inflammatory response and contribute to organ injury and mortality in animal models of severe sepsis. However, the downstream mechanisms responsible for TLR-mediated septic injury are poorly understood. In this article, we show that activation of TLR2, TLR3, and TLR4 markedly enhanced complement factor B (cfB) synthesis and release by macrophages and cardiac cells. Polymicrobial sepsis, created by cecal ligation and puncture in a mouse model, augmented cfB levels in the serum, peritoneal cavity, and major organs including the kidney and heart. Cecal ligation and puncture also led to the alternative pathway activation, C3 fragment deposition in the kidney and heart, and cfB-dependent C3dg elevation. Bacteria isolated from septic mice activated the serum alternative pathway via a factor D-dependent manner. MyD88 deletion attenuated cfB/C3 upregulation as well as cleavage induced by polymicrobial infection. Importantly, during sepsis, absence of cfB conferred a protective effect with improved survival and cardiac function and markedly attenuated acute kidney injury. cfB deletion also led to increased neutrophil migratory function during the early phase of sepsis, decreased local and systemic bacterial load, attenuated cytokine production, and reduced neutrophil reactive oxygen species production. Together, our data indicate that cfB acts as a downstream effector of TLR signaling and plays a critical role in the pathogenesis of severe bacterial sepsis.

Original languageEnglish
Pages (from-to)5625-5635
Number of pages11
JournalJournal of Immunology
Volume191
Issue number11
DOIs
StatePublished - Dec 1 2013

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    Zou, L., Feng, Y., Li, Y., Zhang, M., Chen, C., Cai, J., Gong, Y., Wang, L., Thurman, J. M., Wu, X., Atkinson, J. P., & Chao, W. (2013). Complement factor B is the downstream effector of TLRs and plays an important role in a mouse model of severe sepsis. Journal of Immunology, 191(11), 5625-5635. https://doi.org/10.4049/jimmunol.1301903