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The Complement-Targeted Inhibitor Mini-FH Protects against Experimental Periodontitis via Both C3-Dependent and C3-Independent Mechanisms.

Xiaofei LiHui WangChristoph Q SchmidtViviana P FerreiraDespina YancopoulouDimitrios C MastellosJohn D LambrisGeorge Hajishengallis
Published in: Journal of immunology (Baltimore, Md. : 1950) (2023)
A minimized version of complement factor H (FH), designated mini-FH, was previously engineered combining the N-terminal regulatory domains (short consensus repeat [SCR]1-4) and C-terminal host-surface recognition domains (SCR19-20) of the parent molecule. Mini-FH conferred enhanced protection, as compared with FH, in an ex vivo model of paroxysmal nocturnal hemoglobinuria driven by alternative pathway dysregulation. In the current study, we tested whether and how mini-FH could block another complement-mediated disease, namely periodontitis. In a mouse model of ligature-induced periodontitis (LIP), mini-FH inhibited periodontal inflammation and bone loss in wild-type mice. Although LIP-subjected C3-deficient mice are protected relative to wild-type littermates and exhibit only modest bone loss, mini-FH strikingly inhibited bone loss even in C3-deficient mice. However, mini-FH failed to inhibit ligature-induced bone loss in mice doubly deficient in C3 and CD11b. These findings indicate that mini-FH can inhibit experimental periodontitis even in a manner that is independent of its complement regulatory activity and is mediated by complement receptor 3 (CD11b/CD18). Consistent with this notion, a complement receptor 3-interacting recombinant FH segment that lacks complement regulatory activity (specifically encompassing SCRs 19 and 20; FH19-20) was also able to suppress bone loss in LIP-subjected C3-deficient mice. In conclusion, mini-FH appears to be a promising candidate therapeutic for periodontitis by virtue of its ability to suppress bone loss via mechanisms that both include and go beyond its complement regulatory activity.
Keyphrases
  • bone loss
  • wild type
  • mouse model
  • blood pressure
  • physical activity
  • metabolic syndrome
  • type diabetes
  • skeletal muscle
  • sleep apnea
  • cell free