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

Abstract

Recent studies provide a functional link between kallikrein 6 (Klk6) and the development and progression of disease in multiple sclerosis patients and in its murine models. To evaluate the involvement of additional kallikrein family members, we compared Klk6 expression to 4 other kallikreins (Klk1, Klk7, Klk8 and Klk10) in the brain and spinal cord of mice infected with Theiler’s murine encephalomyelitis virus (TMEV), an experimental model of progressive MS. The robust upregulation of Klk6 and Klk8 in the brain during the acute phase of viral encephalitis and in the spinal cord during disease development and progression points to their participation in inflammation, demyelination and progressive axon degeneration. More limited changes in Klk1, Klk7, and Klk10 were also observed. In addition, Klk1, Klk6, and Klk10 were dynamically regulated in T-cells in vitro as a recall response to viral antigen and in activated monocytes pointing to their activities in the development of adaptive and innate immune function. Together, these results point to overlapping and unique roles for multiple kallikreins in the development and progression of virus-mediated central nervous system inflammatory demyelinating disease, including activities in the development of the adaptive and innate immune response, in demyelination and in progressive axon degeneration.

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

“…Prior studies support the idea that thrombin can be produced by CNS cells endogenously (Dihanich et al, 1991) with elevations after injury, including SCI (Citron et al, 2000; Yoon et al, 2013), ischemia (Riek-Burchardt et al, 2002; Chen et al, 2012; Rajput et al, 2014), and in Alzheimers (Arai et al, 2006). Furthermore, the expression of another PAR1 agonist, neurosin (Vandell et al, 2008), was also significantly elevated after SCI with expression not only by astrocytes, but also activated monocytes/microglia as we have previously reported in other models of experimental SCI (Scarisbrick et al, 1997; Scarisbrick et al, 2002; Blaber et al, 2004; Scarisbrick et al, 2006; Scarisbrick et al, 2012b; Yoon et al, 2013; Panos et al, 2014) and in cases of human SCI as long as 5 years after the initial insult (Radulovic et al, 2013). While elevations in thrombin, neurosin and PAR1 occurred across the injury continuum, thrombin levels were maximal acutely pointing to key roles in the early injury response.…”

Kallikreins – The melting pot of activity and function

“…In addition to cleaving myelin proteins such as the myelin basic protein, KLK6 can cleave components of the blood–brain barrier, such as laminin, fibronectin and collagens, and can induce inflammation via the activation of cell-surface PARs [150]. Studies show that PAR2 modulates neuro-inflammation by enhancing demyelination and that application of KLK6-inactivating antibodies can reduce the pathobiological role of KLK6 [151, 152]. …”

Role of Immunity and Inflammation in the Pathophysiology of Neurodegenerative Diseases

“…The most common viral models used in research are the Theiler's murine encephalomyelitis virus (TMEV) and the mouse hepatitis virus (MHV) [7,31]. Since the virus directly targets neurons and induces neuronal loss as well as excessive immune response in the CNS, the viral model can be used to study inflammation in the context of neurodegeneration [29,31]. Furthermore, transgenic and knockout animal models have also been used to study the relationship between inflammatory, infectious and autoimmune CNS diseases [32].…”