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.

Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis

“…Of particular significance to MS, Klk6 rapidly hydrolyzes myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) as well as laminin, fibronectin and heat-denatured collagen, key components of the blood-brain barrier (Bernett et al, 2002; Blaber et al, 2002, 2004; Scarisbrick et al, 2002). Taken together, these data support the hypothesis that Klk6 is a key player in multiple aspects of the ‘MS degradome’ (Scarisbrick, 2008) and may therefore serve as a useful therapeutic target (Scarisbrick et al, 2002, 2011, 2012a,b; Burda et al, 2013; Yoon et al, 2013, 2015). …”

Differential expression of multiple kallikreins in a viral model of multiple sclerosis points to unique roles in the innate and adaptive immune response

“…Thus, at sites of viral infection, viral capsid-induced elevations in T-cell kallikreins may act in an autocrine or paracrine fashion to enhance and prolong the chronic inflammatory response. The current results suggest additional study regarding the roles of Klk1, Klk6, Klk10, and potentially other kallikrein family members (Scarisbrick 2008; Scarisbrick 2012), as well as potential regulatory elements (Scarisbrick et al 2006) in the development of virus-directed T-cell responses is needed, with results likely to shed new light on novel immune regulatory mechanisms relevant to inflammatory demyelinating disease.…”

Targeting the thrombin receptor modulates inflammation and astrogliosis to improve recovery after spinal cord injury

“…Elevations can occur due to protease leakage across a damaged blood brain barrier or as a consequence of up regulation by CNS endogenous cells (Cunningham et al, 1993; Scarisbrick et al, 1997; Gingrich and Traynelis, 2000; Scarisbrick et al, 2002; Suo et al, 2002; Junge et al, 2003; Scarisbrick et al, 2008; Chen et al, 2012; Drucker et al, 2013). Thrombin is known well for its ability to cleave soluble fibrinogen releasing fibrin monomers that support hemostasis.…”

“…Given the abundance of PAR1 activators at sites of CNS injury (Scarisbrick, 2008) taken with their activities in neuropathogenesis we sought to establish whether global targeting of PAR1 would result in improved neurobehavioral outcomes after experimental traumatic SCI. This was accomplished by comparing cellular, molecular and sensorimotor outcomes after contusion compression SCI in PAR1 knockout compared to wild type mice.…”