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Matrix metalloproteinase-8 (MMP-8) regulates the activation of hepatic stellate cells (HSCs) through the ERK-mediated pathway

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Abstract

Hepatic stellate cells (HSCs) are known to play a key role in the progression of liver fibrosis by producing excessive extracellular matrix (ECM). Matrix metalloproteinases (MMPs) belong to a family of endopeptidases, which have a well-established role in the degradation of ECM. Our study suggests that, besides the degradation of the extracellular matrix, matrix metalloproteinase-8 (MMP-8) has a non-canonical role in activating the quiescent HSCs to myofibroblasts by regulating the expression of Col1A1 and αSMA. We have identified that MMP-8 secreted from macrophages as a response to LPS stimulation activates HSCs via ERK1/2-dependent pathway. In addition to this, we determined that MMP-8 may regulate the homodimerization of c-Jun in LX-2 cells, during the trans-differentiation process from quiescent HSC to activate myofibroblasts. Macrophage-released MMP-8 plays a master role in activating the dormant HSCs to activate myofibroblasts through the Erk-mediated pathway and Jun cellular translocation leading to liver fibrosis. Significance MMP-8 can be used as a therapeutic target against liver fibrosis.

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Acknowledgements

We would like to thank the Council for Scientific and Industrial Research (CSIR) for providing financial assistance through the grant (37/1664/15/EMR-11). The authors also gratefully acknowledge the Indian Institute of Technology Indore (IITI) for providing facilities and other support. We are thankful to Sajjan Rajpoot and Anjali Roy for their contribution in making reviewing the revised manuscript figures and text. Authors are thankful to Institute of Liver and Biliary Sciences (ILBS), New Delhi, for providing human hepatic stellate cells lines (LX-2).

Funding

Financial assistance for this work was provided by the Council for Scientific and Industrial Research (CSIR) through the grant (37/1664/15/EMR-11).

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  1. Discipline of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol, Indore, 453552, India

    Adnan Naim & Mirza S. Baig

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  1. Adnan Naim
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  2. Mirza S. Baig
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MSB conceived the study. AN did the experimental work. MSB wrote and reviewed the manuscript.

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Correspondence to Mirza S. Baig.

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11010_2020_3705_MOESM1_ESM.jpg

Supplementary Fig. 1—Expression of IL-12 and IL-23 in LX-2 cells post-stimulation with LPS conditioned media. (A) Expression of IL-12 in LX-2 cells cultured in LPS stimulated conditioned media and in the presence of MMP-8 and ERK inhibitor. (B) Expression of IL-23 in LX-2 cells cultured in LPS stimulated conditioned media and in the presence of MMP-8 and ERK inhibitor. (JPG 68 kb)

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Naim, A., Baig, M.S. Matrix metalloproteinase-8 (MMP-8) regulates the activation of hepatic stellate cells (HSCs) through the ERK-mediated pathway. Mol Cell Biochem 467, 107–116 (2020). https://doi.org/10.1007/s11010-020-03705-x

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