Genetic and therapeutic targeting of properdin in mice prevents complement-mediated tissue injury
Yuko Kimura, … , Takashi Miwa, Wen-Chao Song
Yuko Kimura, … , Takashi Miwa, Wen-Chao Song
Published September 1, 2010
Citation Information: J Clin Invest. 2010;120(10):3545-3554. https://doi.org/10.1172/JCI41782.
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Research Article Inflammation

Genetic and therapeutic targeting of properdin in mice prevents complement-mediated tissue injury

Abstract

The alternative pathway (AP) of complement activation is constitutively active and must be regulated by host proteins to prevent autologous tissue injury. Dysfunction of AP regulatory proteins has been linked to several human inflammatory disorders. Properdin is a positive regulator of AP complement activation that has been shown to extend the half-life of cell surface–bound C3 convertase C3bBb; it may also initiate AP complement activation. Here, we demonstrate a critical role for properdin in autologous tissue injury mediated by AP complement activation. We identified myeloid lineage cells as the principal source of plasma properdin by generating mice with global and tissue-specific knockout of Cfp (which encodes properdin) and by generating BM chimeric mice. Properdin deficiency rescued mice from AP complement–mediated embryonic lethality caused by deficiency of the membrane complement regulator Crry and markedly reduced disease severity in the K/BxN model of arthritis. Ab neutralization of properdin in WT mice similarly ameliorated arthritis development, whereas reconstitution of properdin-null mice with exogenous properdin restored arthritis sensitivity. These data implicate systemic properdin as a key contributor to AP complement–mediated injury and support its therapeutic targeting in complement-dependent human diseases.

Authors

Yuko Kimura, Lin Zhou, Takashi Miwa, Wen-Chao Song

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Figure 1

Properdin deficiency ameliorates K/BxN arthritis.

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Properdin deficiency ameliorates K/BxN arthritis. Arthritis was induced ...
Arthritis was induced in Cfp–/– mice and their WT littermate controls by i.p. injection of K/BxN mouse serum (A and B; n = 10 per group) or IgG (D and E; n = 7 [WT], 11 [Cfp–/–]) on days 0 and 2. Ankle thickening (A and D) and clinical index (B and E) were recorded daily. Ankle thickness was measured in millimeters by a caliper and presented as change from day 0. Clinical index was determined as follows: 1 point for each inflamed and swollen paw; 0.5 points for each paw with mild swelling/redness or a few affected digits. *P < 0.05 versus WT, nonparametric Wilcoxon/Kruskal-Wallis test. (C) IL-1β levels in tissue homogenates of ankles (n = 3 per group) at days 3 and 8 after K/BxN serum transfer. P values were determined by Student’s t test. (F) Representative images of arthritis in WT and Cfp–/– mice at day 7 after K/BxN IgG transfer showing gross anatomy of hind limbs (top), joint histology with H&E staining (middle), and C3 staining (bottom). Original magnification, ×40. (G) Semiquantitative scoring of histopathology and C3 deposition in the joints of WT and Cfp–/– mice at day 7 after K/BxN IgG transfer. A total of 11 hind limb joints from 6 mice in each group of mice was analyzed; horizontal bars denote mean. **P < 0.001, Student’s t test.