title: Complement factor B is the downstream effector of TLRs and plays an important role in a mouse model of severe sepsis.
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.
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
authors.forename: Lin
authors.initials: L
authors.lastname: Zou
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Chan
authors.initials: C
authors.lastname: Chen
authors.forename: Jiayan
authors.initials: J
authors.lastname: Cai
authors.forename: Yu
authors.initials: Y
authors.lastname: Gong
authors.forename: Larry
authors.initials: L
authors.lastname: Wang
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Thurman
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wu
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
authors.forename: Wei
authors.initials: W
authors.lastname: Chao
mesh_terms: D000818:Animals; D002432:Cecum / Q000601:surgery; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D003176:Complement C3 / Q000378:metabolism; D011415:Complement Factor B / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism
chemical_list: D003176:Complement C3; D053594:Myeloid Differentiation Factor 88; D017382:Reactive Oxygen Species; D051193:Toll-Like Receptors; D011415:Complement Factor B