Complement factor H–deficient mice develop spontaneous hepatic tumors
Jennifer Laskowski, … , Raphael A. Nemenoff, Joshua M. Thurman
Jennifer Laskowski, … , Raphael A. Nemenoff, Joshua M. Thurman
Published May 5, 2020
Citation Information: J Clin Invest. 2020;130(8):4039-4054. https://doi.org/10.1172/JCI135105.
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Research Article Immunology Oncology

Complement factor H–deficient mice develop spontaneous hepatic tumors

Abstract

Hepatocellular carcinoma (HCC) is difficult to detect, carries a poor prognosis, and is one of few cancers with an increasing yearly incidence. Molecular defects in complement factor H (CFH), a critical regulatory protein of the complement alternative pathway (AP), are typically associated with inflammatory diseases of the eye and kidney. Little is known regarding the role of CFH in controlling complement activation within the liver. While studying aging CFH-deficient (fH–/–) mice, we observed spontaneous hepatic tumor formation in more than 50% of aged fH–/– males. Examination of fH–/– livers (3–24 months) for evidence of complement-mediated inflammation revealed widespread deposition of complement-activation fragments throughout the sinusoids, elevated transaminase levels, increased hepatic CD8+ and F4/80+ cells, overexpression of hepatic mRNA associated with inflammatory signaling pathways, steatosis, and increased collagen deposition. Immunostaining of human HCC biopsies revealed extensive deposition of complement fragments within the tumors. Investigating the Cancer Genome Atlas also revealed that increased CFH mRNA expression is associated with improved survival in patients with HCC, whereas mutations are associated with worse survival. These results indicate that CFH is critical for controlling complement activation in the liver, and in its absence, AP activation leads to chronic inflammation and promotes hepatic carcinogenesis.

Authors

Jennifer Laskowski, Brandon Renner, Matthew C. Pickering, Natalie J. Serkova, Peter M. Smith-Jones, Eric T. Clambey, Raphael A. Nemenoff, Joshua M. Thurman

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Figure 7

Recombinant factor H binds in the sinusoids of fH–/– mice.

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Recombinant factor H binds in the sinusoids of fH–/– mice. (A and B) rmC...
(A and B) rmCFH binds within the sinusoids of fH–/– mice in a continuous pattern (A, left), but is reduced and punctate in WT mice (A, right). Scale bars: 20 μm. (B) Quantification of bound rmCFH. ****P < 0.0001, t = 12.98, df = 4.544; 2-tailed t test with Welch’s correction; mean ± SEM. For A and B, n = 5 males per group (WT, 9 months; fH–/–, 7 months). (C–E) Enlarged view of fH–/– image identified by dashed white box in A. Abundant rmCFH deposition (arrowhead) near iC3b/C3d (C, turquoise) and C3b (D, red). Intermittent C3b (C and E; arrows) colocalized with linear iC3b/C3d. Scale bars: 10 μm. (F) Compared with unmanipulated fH–/–, rmCFH-reconstituted fH–/– mice have reduced sinusoidal C3b (****P < 0.0001, t = 8.424, df = 7.179) and increased iC3b/C3d, demonstrating rmCFH-mediated conversion of C3b to iC3b/C3d (**P = 0.0015, t = 4.729, df = 7.931; 2-tailed t test with Welch’s correction; mean ± SEM; n = 5 males [7 months] per group). (G and H) rmCFH colocalized with COL4 (G) and MECA-32 (H, arrows) in fH–/– sinusoids, but not on the large vasculature (vascular lumen denoted by asterisks). Nuclei stained with DAPI (blue). Scale bars: 10 μm; n = 5. Representative images shown from 4 independent experiments.