A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity. (Nature Medicine 2014, 20(5):493-502)

報告日期: 2014/10/28
報告時間: 5:10/6:00
報告學生: 鄭怡琳(以英文報告)
講評老師: 張堯
附件下載: 下載[1434-1412237732-1.pdf] 

A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity

Marchant, D. J. et al.

Nat. Med. 20: 493-502 (2014).

Student: Yi-Lin Cheng (鄭怡琳)             Time: 17:10~18:00, Oct. 28, 2014

Commentator: Dr. Yao Chang (張堯博士)    Place: Room 602

Abstract

Matrix metalloproteinase-12 (MMP-12) is known as a secreted protease that degrades extracellular matrix and is involved in inflammatory tissue destruction conventionally.1 However, more and more new substrates and new function of MMPs are found in regulation of extracellular homeostasis and innate immunity.2 Like other MMPs, MMP-12 also plays a protective role in antituomorigenic, anti-inflammatory and antibacterial activities. However, despite MMPs regulate macrophage chemotaxis and activation by chemokine cleavge, whether MMP-12 directly modulates antiviral immunity is still unknown. In this study, the authors demonstrated that intracellular MMP-12 binds to NFKBIA promoter leading to secretion of interferon-α (IFN-α), which is essential for antiviral activity, and extracellular MMP-12 cleaves off the IFN-α receptor 2 binding site of systemic IFN-α. First, they found that reduction of survival rates, increase of viral titers, and defect of IFN-α secretion from infected cells were observed in MMP-12-/- mice infected with coxsackievirus type B3 or respiratory syncytial virus. MMP-12-/- cells also showed lower expression of IκBα, which is a key mediator of innate immunity, compared with wild-type cells. Inhibiting IκBα pharmacologically or genetically suppressed secretion of IFN-α. Interestingly, they also demonstrated that MMP-12, which is secreted by macrophages, trafficked to the nucleus of surrounding cells resulting in elevation of MMP-12 expression in the MMP-12-diffcient cells. Using chromatin immunoprecipitation combined with whole-genome sequence analysis, they found that NFKBIA promoter is a target of MMP-12 after viral infection. In addition, they identified a number of substrates, including the highest MMP-12 DNA-binding peaks, PSME3 and SPARCL1 genes, repressed by MMP-12 binding to the exon of substrates and MMP-12-mediated cleavage of the substrate proteins. They called this group of proteins as dual-regulated substrates. Despite intracellular MMP-12 promoted NFKBIA transcription leading to IFN-α export, extracellular MMP-12 cleaved systemic IFN-α. Finally, the authors treated the infected mice with a membrane impermeable inhibitor (RXP470.1) of MMP-12, which won’t affect intracellular MMP-12. The results showed that viral replication was significantly reduced in the RXP470.1-treated group. These results suggest that inhibiting extracellular MMP-12 to enhance IFN-α expression could be a new strategy for treatment of viral infection.

References

  1. Belvisi, M.G. & Bottomley, K.M. The role of matrix metalloproteinases (MMPs) in the pathophysiology of chronic obstructive pulmonary disease (COPD): a therapeutic role for inhibitors of MMPs? Inflamm. Res. 52, 95–100 (2003).
  2. Parks, W.C., Wilson, C.L. & Lopez-Boado, Y.S. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. 4, 617–629 (2004).