Abstract 718: Mammalian Serine Protease Inhibitor (Serpin), Neuroserpin, Targets Thromblytic Proteases to Reduce Inflammation, Atherogenesis and T Helper Lymphocyte Activation
Rationale: Next to Macrophages, T-cells have been identified has the most abundant population of immune cells in atherosclerotic plaque. Surface markers expressed by T-cells in plaque demonstrate both antigen-dependent and non-antigen dependent chronic T cell activation. The TH1 (T helper) lymphocyte subtype is a major contributor to vascular inflammation, with secretion of IFNγ, IL-2 and TNF. Serpins that regulate thrombotic and thrombolytic pathways also regulate inflammatory responses. Serp-1 is a highly potent anti-inflammatory and anti-atherogenic myxomaviral serpin, currently in clinical trial, that inhibits tPA, uPA, plasmin and factor Xa.
Methods: We have examined the capacity of a native mammalian serpin, Neuroserpin (NSP), that inhibits tPA to block inflammation and plaque growth in mouse models of aortic transplant. In prior work, NSP was reported to reduce stroke size. Pro-inflammatory TH1 and anti-inflammatory TH2 subpopulations were analyzed after MCP-1 chemokine injection in mouse ascites and blood. TH2 IL-4 and TH1 IFNγ levels were measured after treatment with each serpin.
Results: NSP treatment significantly reduced plaque growth in C57Bl/6 PAI-1 deficient (PAI-1−/−) mice (18 mice, P<.002) at a dose of 1.5μg given immediately after aortic transplant. Plaque inhibition was associated with significant inhibition of monocyte (MC) (p<0.004) and lymphocyte (p<0.002) invasion. NSP increased the ratio of TH2 anti-inflammatory to TH1 pro-inflammatory T lymphocyte subpopulation activity when compared to other serpins in C57Bl/6 (normal) mouse blood (p<0.002) and ascites (p<0.004) samples. The TH2/TH1 ratio was unchanged in uPAR receptor deficient (uPAR−/−) mice. Conversely an inactive NSP-PP mutant increased MC (p<0.004) and lymphocyte (p<0.009) invasion in normal mice and increased TH2/TH1 in uPAR−/− mouse ascites (p<0.003), but not in wild type mice.
Neuroserpin, a naturally occurring mammalian serpin that selectively inhibits tPA, reduced inflammation and plaque growth in mouse and rat aortic transplant models with associated increases in anti-inflammatory TH2 responses.
Neuroserpin represents a new and naturally expressed mammalian serpin with potential therapeutic anti-inflammatory activity.