Complement factor H–deficient mice develop spontaneous hepatic tumors
Jennifer Laskowski, Brandon Renner, Matthew C. Pickering, Natalie J. Serkova, Peter M. Smith-Jones, Eric T. Clambey, Raphael A. Nemenoff, Joshua M. Thurman
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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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 5

Inflammation and leukocyte infiltration in fH–/– livers.

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Inflammation and leukocyte infiltration in fH–/– livers. (A and B) Large...
(A and B) Large pockets of inflammatory infiltrate captured by multiplex imaging in fH–/– (A, left, and B) but not in WT livers (A, right). Nuclei stained with DAPI (blue). Original magnification ×200. Scale bars: 50 μm (A), 10 μm (B). (C) Increased populations of each cell type in fH–/– livers compared with WT. F4/80+, ***P = 0.0002, t = 6.802, df = 7.559; CD8+, **P = 0.0069, t = 4.949, df = 4.178; CD4+, P = 0.1228; CD3+, P = 0.1868; Foxp3+/CD4+, P = 0.1409; B220+, P = 0.2894. For A–C, n = 5 males (3 months) per group; 2-tailed t test with Welch’s correction; mean ± SEM. (D) By flow cytometry, young fH–/– males have fewer hepatic neutrophils compared with WT (P = 0.2067) and fH–/–fB–/– (**P = 0.0051, t = 5.596, df = 3.963) mice. Neutrophils trend higher in fH–/– males with liver tumors compared with those without (P = 0.061). Data were analyzed by unpaired, 2-tailed t test with Welch’s correction; mean ± SEM; n = 3 per group (fH–/– and WT, 3 months); n = 4 per group (fH–/– and fH–/–fB–/–, 4 months); n = 4 and 2 (fH–/– with and without liver tumors, respectively; 22–24 months). (E) Clusters of Ly6G+ cells (pink) are observed in livers with multiple tumor foci (arrows). Scale bars: 50 μm; n = 10 independent fH–/– liver tumors. Nuclei stained with DAPI (turquoise). All images are representative of 2 independent experiments.