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.…”

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.…”

Kallikrein-related peptidases protein expression in lymphoid tissues suggests potential implications in immune response

“…Other studies have previously demonstrated the integral role of KLK10 in T-cell responses to viral antigens and the development of pro-inflammatory responses, as mediated by the adaptive immune system[40]. Recent immunopeptidome analyses demonstrated that KLK10 protein is amongst the presented immunogenic epithelial ovarian cancer antigens and is a target for antigen-specific immunotherapy[41].Overall, our study revealed the possible implications of KLK expression and regulation in immune cells.…”

Codonopsis pilosula-derived glycopeptide dCP1 promotes the polarization of tumor-associated macrophage from M2-like to M1 phenotype

“…3 A) that there are 1,836 up-regulated genes and 1,530 down-regulated genes, and the distribution of differentially expressed genes on the left and right sides of the volcano map is basically balanced. The top 10 genes with the highest significance among the up-regulated and down-regulated genes were labeled, and among the 10 genes with the most significant up-regulated, the expression products of Siglec-1 [ 53 ], KLK9 [ 54 ], CFP [ 55 ], PMFI [ 56 ], KLk8 [ 57 ] and TUBA1B [ 58 ] have pro-inflammatory effects. Among the 10 most significantly down-regulated genes, Crispld2 [ 59 – 61 ], MAP4K3 [ 62 ] and Nfkbiz [ 63 ] had anti-inflammatory effects.…”

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.…”

Kallikrein-related peptidases protein expression in lymphoid tissues suggests potential implications in immune response

“…Other studies have previously demonstrated the integral role of KLK10 in T-cell responses to viral antigens and the development of pro-inflammatory responses, as mediated by the adaptive immune system[40]. Recent immunopeptidome analyses demonstrated that KLK10 protein is amongst the presented immunogenic epithelial ovarian cancer antigens and is a target for antigen-specific immunotherapy[41].Overall, our study revealed the possible implications of KLK expression and regulation in immune cells.…”

Codonopsis pilosula-derived glycopeptide dCP1 promotes the polarization of tumor-associated macrophage from M2-like to M1 phenotype

“…3 A) that there are 1,836 up-regulated genes and 1,530 down-regulated genes, and the distribution of differentially expressed genes on the left and right sides of the volcano map is basically balanced. The top 10 genes with the highest significance among the up-regulated and down-regulated genes were labeled, and among the 10 genes with the most significant up-regulated, the expression products of Siglec-1 [ 53 ], KLK9 [ 54 ], CFP [ 55 ], PMFI [ 56 ], KLk8 [ 57 ] and TUBA1B [ 58 ] have pro-inflammatory effects. Among the 10 most significantly down-regulated genes, Crispld2 [ 59 – 61 ], MAP4K3 [ 62 ] and Nfkbiz [ 63 ] had anti-inflammatory effects.…”

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.…”

Kallikrein-related peptidases protein expression in lymphoid tissues suggests potential implications in immune response

“…Other studies have previously demonstrated the integral role of KLK10 in T-cell responses to viral antigens and the development of pro-inflammatory responses, as mediated by the adaptive immune system[40]. Recent immunopeptidome analyses demonstrated that KLK10 protein is amongst the presented immunogenic epithelial ovarian cancer antigens and is a target for antigen-specific immunotherapy[41].Overall, our study revealed the possible implications of KLK expression and regulation in immune cells.…”

Codonopsis pilosula-derived glycopeptide dCP1 promotes the polarization of tumor-associated macrophage from M2-like to M1 phenotype

“…3 A) that there are 1,836 up-regulated genes and 1,530 down-regulated genes, and the distribution of differentially expressed genes on the left and right sides of the volcano map is basically balanced. The top 10 genes with the highest significance among the up-regulated and down-regulated genes were labeled, and among the 10 genes with the most significant up-regulated, the expression products of Siglec-1 [ 53 ], KLK9 [ 54 ], CFP [ 55 ], PMFI [ 56 ], KLk8 [ 57 ] and TUBA1B [ 58 ] have pro-inflammatory effects. Among the 10 most significantly down-regulated genes, Crispld2 [ 59 – 61 ], MAP4K3 [ 62 ] and Nfkbiz [ 63 ] had anti-inflammatory effects.…”