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. 2001 Jun;158(6):2117-25.
doi: 10.1016/s0002-9440(10)64683-4.

Murine gammaherpesvirus-68 infection causes multi-organ fibrosis and alters leukocyte trafficking in interferon-gamma receptor knockout mice

B Ebrahimi  1 , B M Dutia, D G Brownstein, A A Nash
Affiliations

Murine gammaherpesvirus-68 infection causes multi-organ fibrosis and alters leukocyte trafficking in interferon-gamma receptor knockout mice (VSports最新版本)

B Ebrahimi et al. Am J Pathol. 2001 Jun.

VSports - Abstract

Murine gammaherpesvirus-68 (MHV-68) infection in interferon-gamma receptor knockout mice (IFN-gammaR(-)/(-)) results in splenic fibrosis and excessive loss of splenocytes. In our present study we found that MHV-68 infection in IFN-gammaR(-)/(-) mice also resulted in fibrosis and atrophy of the mediastinal lymph nodes, interstitial pulmonary fibrosis and fibrotic changes in the liver. Atrophy and cellular depletion of the spleen in IFN-gammaR(-)/(-) was not the result of increased cell death. The loss of splenocytes in IFN-gammaR(-)/(-) mice, which was most evident on day 23 after infection, correlated with an increase in the number of leukocytes in peripheral blood. At the peak of leukocytosis, on day 23 after infection, peripheral blood cells from infected IFN-gammaR(-)/(-) mice were unable to traffic through the fibrosed spleens of IFN-gammaR(-)/(-) mice but were able to enter the spleens of wild-type mice. This indicates that leukocytosis was in part the result of emigration of cells from the spleen and their subsequent exclusion of re-entry at the height of fibrosis. Significant cytokine and chemokine changes were observed in spleens of IFN-gammaR(-)/(-) mice. IFN-gamma, tumor necrosis factor-alpha (TNF-alpha ), TNF-beta, interleukin-1beta (IL-1beta), transforming growth factor-beta1 (TGF-beta1), lymphotactin, and MIP-1beta were elevated on day 14 after infection whereas chemokines IP-10 and MIG were significantly reduced VSports手机版. These changes suggest a role for dysregulated cytokines and chemokines in severe organ-specific fibrosis with implications for immune-mediated fibrotic disorders. .

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Figures

Figure 1.
Figure 1.
Pathological changes in IFN-γR−/− mice infected with MHV-68. Pathological changes on days 14 (I), 23 (B, E, and G), and 45 (C, F, and H) after infection with MHV-68. A: Normal spleen before infection. B: Fibrosis in sinusoids of red pulp. C: Partial resolution of fibrosis and contraction of residual fibrous tissue. D: Normal MLN before infection. E: Widespread fibrosis in MLN. F: Resolving fibrosis and increased cellularity in MLN. G: Periportal infiltrate encroaching on portal vein. H: Partial resolution of hepatic changes I: Interstitial pulmonary fibrosis. Sections A and D were stained with H&E, and sections B, C, and E–I were stained with Masson’s trichrome. Representative sections are from five mice per each time point. Original magnifications: A–F, ×50; G–H, ×80; I, ×250.
Figure 2.
Figure 2.
Splenic cellularity in MHV-68-infected mice. In contrast to wild-type mice, spleens of IFN-γR−/− mice were severely depleted by day 23 after infection but showed signs of partial repopulation by day 45 after infection. *, Significantly different from wild-type mice; P < 0.05. Numbers represent mean ± SD (n = 3). ♦, wild-type mice; ▪, IFN-γR−/− mice.
Figure 3.
Figure 3.
Apoptotic death in spleen. Spleens were fixed in formal saline and stained for TUNEL. All TUNEL-positive cells were counted on each section. Numbers of TUNEL-positive cells were comparable between IFN-γR−/− and wild-type mice during the course of infection. Numbers represent mean ± SD. ♦, wild-type mice; ▪, IFN-γR−/− mice.
Figure 4.
Figure 4.
Hematological changes in MHV-68-infected mice. Venous blood was analyzed before infection and throughout the course of infection with MHV-68 at BI. ♦, wild-type mice; ▪, IFN-γR−/− mice; *, significantly elevated in IFN-γR−/− mice; P < 0.05. Numbers represent mean ± SD (n = 5).
Figure 5.
Figure 5.
Inhibition of leukocyte trafficking through the severely fibrosed spleens. FACS analyses of splenocytes from (A) wild-type mice on day 23 after infection, (B) IFN-γR−/− mice on day 23 after infection, and (C) IFN-γR−/− mice on day 10 after infection injected 24 hours previously with labeled PBL from IFN-γR−/− mice after 23 days after infection. Data are representatives of three mice per each group.
Figure 6.
Figure 6.
Splenic expression of cytokines and chemokines in MHV-68-infected mice. Gene-specific multiprobe RPA sets were used to measure the levels of splenic cytokines and chemokines. Representative autoradiographs: A, ML11 set (7 day exposure); B, CCR7 set (7 day exposure); C, ML26 set (overnight exposure to show elevated expression of TGF-β1 in IFN-γR−/− mice); D, mCK5 set (14 day exposure to show elevated levels of LTN in IFN-γR−/− mice); E, Significant fold changes in spleens of IFN-γR−/− mice compared to wild-type mice on day 14 after infection. Data were obtained from five mice per group per each time point. Mean ratios of optical density (633 nm) of cytokine/chemokine mRNA levels were calculated against the mean signals for housekeeping genes, L32, and GAPDH.
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