The multiple sclerosis degradome: enzymatic cascades in development and progression of central nervous system inflammatory disease

Abstract

An array of studies implicate different classes of protease and their endogenous inhibitors in multiple sclerosis (MS) pathogenesis based on expression patterns in MS lesions, sera, and/or cerebrospinal fluid (CSF). Growing evidence exists regarding their mechanistic roles in inflammatory and neurodegenerative aspects of this disease. Proteolytic events participate in demyelination, axon injury, apoptosis, and development of the inflammatory response including immune cell activation and extravasation, cytokine and chemokine activation/inactivation, complement activation, and epitope spreading. The potential significance of proteolytic activity to MS therefore relates not only to their potential use as important biomarkers of disease activity, but additionally as prospective therapeutic targets. Experimental data indicate that understanding the net physiological consequence of altered protease levels in MS development and progression necessitates understanding protease activity in the context of substrates, endogenous inhibitors, and proteolytic cascade interactions, which together make up the MS degradome. This review will focus on evidence regarding the potential physiologic role of those protease families already identified as markers of disease activity in MS; that is, the metallo-, serine, and cysteine proteases.

Fig. 1

The MS degradome is that set of proteases, their inhibitors, and substrates that contribute to the development and progression of MS. Proteolysis plays a direct role in ECM turnover, immune cell extravasation, myelinolysis, and injury to oligodendrocytes (OLG) and axons. Limited proteolytic events also play key roles in regulating the activity and expression of cytokines, chemokines, and their receptors. Combined, these proteolytic activities promote the release of immunogenic peptides, antigen presentation, and immune cell activation. In turn, these events collectively affect the availability of proteases, their inhibitors, and substrates and, therefore, the development and progression of CNS inflammatory demyelinating disease