Plasminogen activators in multiple sclerosis lesions: implications for the inflammatory response and axonal damage

Area of Science:

• Neuroscience
• Biochemistry
• Immunology

Background:

• The plasminogen activator (PA) and matrix metalloprotease (MMP) cascades are involved in tissue remodeling and inflammation.
• Dysregulation of these cascades is implicated in neuroinflammatory diseases like multiple sclerosis (MS).

Purpose of the Study:

• To investigate the functional role of PA and MMP cascade components in the development of MS lesions.
• To quantify changes in specific PA and MMP proteins within MS lesions and normal-appearing white matter.

Main Methods:

• Immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and enzyme activity assays were employed.
• Quantitative analysis of urokinase plasminogen activator (uPA), urokinase receptor (uPAR), plasminogen activator inhibitor-1, MMP-9, and tissue plasminogen activator (tPA) in MS lesions and control tissues.
• Immunolocalization of proteins to specific cell types within lesions.

Main Results:

• Significant increases in uPA, uPAR, and plasminogen activator inhibitor-1 were observed in acute MS lesions and uPAR in normal-appearing white matter.
• uPA, uPAR, and inhibitor-1 were localized to inflammatory cells (mononuclear cells, macrophages).
• MMP-9 increased but was mainly in its inactive pro-form; tPA concentration and activity were reduced in MS specimens.
• Reduced tPA co-localized with fibrin(ogen) on damaged axons.

Conclusions:

• The uPA-uPAR complex on inflammatory cells may promote CNS infiltration in MS, potentially amplified by MMPs degrading the blood vessel matrix.
• Reduced tPA on injured axons could indicate axonal damage or a protective fibrinolytic response.