MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs
Giovanni Sitia, … , Francis V. Chisari, Luca G. Guidotti
Giovanni Sitia, … , Francis V. Chisari, Luca G. Guidotti
Published April 15, 2004
Citation Information: J Clin Invest. 2004;113(8):1158-1167. https://doi.org/10.1172/JCI21087.
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Article Hepatology

MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs

Abstract

We recently showed that antigen-nonspecific inflammatory cells are recruited into the liver when hepatitis B virus (HBV)-specific CTLs are injected into HBV transgenic mice, and that this process amplifies the severity of liver disease. We also showed that the severity of CTL-induced liver disease is ameliorated by the depletion of Gr-1+ cells (Gr-1 is an antigen highly expressed by neutrophils), which, secondarily, abolishes the intrahepatic recruitment of all antigen-nonspecific Gr-1– mononuclear cells (NK and NKT cells, T and B lymphocytes, monocytes, macrophages, dendritic cells) despite the strong induction of chemokine gene expression. Those results suggested that in addition to chemokine expression, CTL-induced functions are necessary for mononuclear cell recruitment to occur. We now report that MMPs known to be produced by Gr-1+ cells are rapidly induced in the livers of CTL-injected mice. The inhibition of MMP activity reduced the intrahepatic recruitment of antigen-nonspecific mononuclear cells and much of the attending liver disease without affecting the migration or antiviral potential of antigen-specific CTLs. The notion that the inhibition of MMP activity is associated with maintenance of antiviral effects but diminished tissue damage may be significant for the development of immunotherapeutic approaches for the treatment of chronic HBV infection.

Authors

Giovanni Sitia, Masanori Isogawa, Matteo Iannacone, Iain L. Campbell, Francis V. Chisari, Luca G. Guidotti

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Recruitment of antigen-nonspecific inflammatory cells into the liver is ...
Recruitment of antigen-nonspecific inflammatory cells into the liver is associated with induced expression and activity of MMP-8 and MMP-9. (A) IHL analysis of transgenic mice from lineage 1.3.32 that were injected with α–Gr-1 and HBsAg-specific CTLs (black bar). The indicated numbers of total IHLs represent the numbers detected in the whole liver. The results were compared with additional groups of transgenic mice that were injected either with saline (NaCl) alone (gray bar) or with CTLs and irrelevant control antibodies (Irr. Ab) (white bar). (B) Total hepatic RNA derived from the same mice was analyzed by RPA for the expression of various MMPs, as indicated. The housekeeping mRNA encoding the ribosomal protein L32 was used to normalize the amount of RNA loaded in each lane. (C) Quantitative phosphor imaging analysis of the same MMP RNAs shown in B. The indicated numbers in the CTL-injected groups (Irr. Ab and α–Gr-1) are displayed as fold induction over NaCl-injected controls (set as 1). The numbers were obtained by dividing each MMP value by the amount of the corresponding housekeeping gene L32 RNA, and they represent the mean of three mice per group. (D) Gelatin-PAGE zymography was performed as described in the Methods on liver extracts from the same mice shown above. (E and F) Collagen type I and gelatin in situ zymography were performed on liver sections from the same mice described above. Cryostat sections were overlaid with a solution containing quenched fluorescent collagen type I (E) or quenched fluorescent gelatin (F), and sections were examined 18 hours later. Collagenase and gelatinase activities become apparent as fluorescence (E and F, middle panels). Note that no detection of collagenase and gelatinase activity was observed in either NaCl-injected controls (E and F, left panels) or CTL-injected mice depleted of Gr-1+ cells (E and F, right panels). Original magnification, ×400.