The mechanisms underpinning concussion, traumatic brain injury (TBI) and chronic traumatic encephalopathy (CTE) are poorly understood. Using neuropathological analyses of brains from teenage athletes, a new mouse model of concussive impact injury, and computational simulations, Tagge et al. show that head injuries can induce TBI and early CTE pathologies independent of concussion.

Several successful pathogens have evolved mechanisms to evade host defense, resulting in the establishment of persistent and chronic infections. One such pathogen, Porphyromonas gingivalis, induces chronic low-grade inflammation associated with local inflammatory bone loss and systemic inflammation manifested as atherosclerosis. P. gingivalis expresses an atypical lipopolysaccharide (LPS) structure containing heterogeneous lipid A species, that exhibit Toll-like receptor-4 (TLR4) agonist or antagonist activity, or are non-activating at TLR4. In this study, we utilized a series of P. gingivalis lipid A mutants to demonstrate that antagonistic lipid A structures enable the pathogen to evade TLR4-mediated bactericidal activity in macrophages resulting in systemic inflammation. Production of antagonistic lipid A was associated with the induction of low levels of TLR4-dependent proinflammatory mediators, failed activation of the inflammasome and increased bacterial survival in macrophages. Oral infection of ApoE−/− mice with the P. gingivalis strain expressing antagonistic lipid A resulted in vascular inflammation, macrophage accumulation and atherosclerosis progression. In contrast, a P. gingivalis strain producing exclusively agonistic lipid A augmented levels of proinflammatory mediators and activated the inflammasome in a caspase-11-dependent manner, resulting in host cell lysis and decreased bacterial survival. ApoE−/− mice infected with this strain exhibited diminished vascular inflammation, macrophage accumulation, and atherosclerosis progression. Notably, the ability of P. gingivalis to induce local inflammatory bone loss was independent of lipid A expression, indicative of distinct mechanisms for induction of local versus systemic inflammation by this pathogen. Collectively, our results point to a pivotal role for activation of the non-canonical inflammasome in P. gingivalis infection and demonstrate that P. gingivalis evades immune detection at TLR4 facilitating chronic inflammation in the vasculature. These studies support the emerging concept that pathogen-mediated chronic inflammatory disorders result from specific pathogen-mediated evasion strategies resulting in low-grade chronic inflammation.

Objective-Studies in humans support a role for the oral pathogen Porphyromonas gingivalis in the development of inflammatory atherosclerosis. The goal of this study was to determine if P. gingivalis infection accelerates inflammation and atherosclerosis in the innominate artery of mice, an artery which has been reported to exhibit many features of human atherosclerotic disease, including plaque rupture.Methods and Results-Apolipoprotein E-deficient (ApoE −/− ) mice were orally infected with P. gingivalis, and Magnetic Resonance Imaging (MRI) was used to monitor the progression of atherosclerosis in live mice. P. gingivalis infected mice exhibited a statistically significant increase in atherosclerotic plaque in the innominate artery as compared to uninfected mice. Polarized light microscopy and immunohistochemistry revealed that the innominate arteries of infected mice had increased lipids, macrophages and T cells as compared to uninfected mice. Increases in plaque, total cholesterol esters and cholesterol monohydrate crystals, macrophages, and T cells were prevented by immunization with heat-killed P. gingivalis prior to pathogen exposure.Conclusions-These are the first studies to demonstrate progression of inflammatory plaque accumulation in the innominate arteries by in-vivo MRI analysis following pathogen exposure, and to document protection from plaque progression in the innominate artery via immunization. * Corresponding Author. Caroline A. Genco, 650 Albany St. Boston, MA 02118, USA,, cgenco@bu.edu. 1 These authors contributed equally to this work. Disclosure None.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptAtherosclerosis. Author manuscript; available in PMC 2012 March 1. We previously demonstrated that oral infection with Porphyromonas gingivalis, the etiological agent of human periodontal disease, accelerates plaque accumulation in the aortic sinus in an apolipoprotein E (ApoE −/− ) mouse model [5,8]. While these studies in the ApoE −/− mouse model have described atherosclerotic lesions of the aortic sinus by histological analysis, intra-plaque rupture or signs of plaque disruption at the aortic sinus have not been reported [9]. In contrast, recent studies have documented the presence of ruptured plaques in the innominate artery of ApoE −/− mice [10][11][12][13][14]. The innominate artery has been reported to undergo a high degree of lesion progression, and lesions in this artery reported to express features characteristic of clinical disease in humans [10,11,[15][16][17]. However, the ability of infectious agents t...

Background-The ability to identify atherosclerotic plaques with a high risk for sudden disruption before stroke or myocardial infarction would be of great utility. We used a rabbit model of controlled atherothrombosis to test whether in vivo MRI can noninvasively distinguish between plaques that disrupt after pharmacological triggering (vulnerable) and those that do not (stable). Methods and Results-Atherosclerosis was induced in male New Zealand White (nϭ17) rabbits by cholesterol diet and endothelial denudation of the abdominal aorta. After baseline (pretrigger) MRI with and without gadolinium contrast, the rabbits underwent 2 pharmacological triggerings to induce atherothrombosis, followed by another MRI 48 hours later (post-triggering). Atherosclerosis was identified by the pretriggered images in all rabbits, and thrombosis was identified in 9 of 17 animals (53%) by post-trigger MRI. After the animals were euthanized, 95 plaques were analyzed; 28 (29.5%) had thrombi (vulnerable) and 67 did not (stable) (70.5%). Pretriggered MRI revealed comparable stenosis in stable and vulnerable plaques, but vulnerable plaques had a larger plaque area (4.8Ϯ1.6 versus 3.0Ϯ1.0 mm 2 ; Pϭ0.01), vessel area (9.2Ϯ3.0 versus. 15.8Ϯ4.9 mm 2 ; Pϭ0.01), and higher remodeling ratio (1.16Ϯ0.2 versus 0.93Ϯ0.2; Pϭ0.01) compared with stable plaques. Furthermore, vulnerable plaques more frequently exhibited (1) positive remodeling (67.8% versus 22.3%; Pϭ0.01), in which the plaque is hidden within the vessel wall instead of occluding the lumen; and (2) enhanced gadolinium uptake (78.6% versus 20.9%; Pϭ0.01) associated with histological findings of neovascularization, inflammation, and tissue necrosis. Conclusions-We demonstrate that in vivo MRI at 3.0 T detects features of vulnerable plaques in an animal model of controlled atherothrombosis. These findings suggest that MRI may be used as a noninvasive modality for localization of plaques that are prone to disruption. (Circ Cardiovasc Imaging. 2010;3:323-332.)Key Words: MRI Ⅲ atherosclerosis Ⅲ thrombosis Ⅲ gadolinium Ⅲ remodeling A cute coronary syndromes (ACS) such as unstable angina pectoris and myocardial infarction are the leading causes of death in the United States. 1 Histological studies demonstrate that ACS are usually triggered by rupture/erosion of vulnerable atherosclerotic plaques, which results in luminal thrombosis. 2,3 X-ray angiographic studies, which do not provide information about plaque composition, suggest that the majority of high-risk plaques cause Ͻ50% luminal narrowing. 4,5 In vivo MRI can estimate the degree of luminal narrowing and identify plaque components. 6 -9 Contrast-enhanced MRI (CE-MRI) using gadolinium-diethylenetriamine penta-acetic acid (Gd-DTPA) has improved the discrimination between the fibrous cap and the lipid core 10,11 and necrotic core 12 and the visualization of coronary atherosclerosis. 13,14 Furthermore, dynamic CE-MRI has shown that uptake of Gd-DTPA is correlated with neovascularization 15,16 and inflammation, 17 both of which are increa...

Background Clinical and epidemiological studies have implicated chronic infections in the development of atherosclerosis. It has been proposed that common mechanisms of signaling via toll like receptors (TLRs) link stimulation by multiple pathogens to atherosclerosis. However, how pathogen specific stimulation of TLR4 contributes to atherosclerosis progression remains poorly understood. Methods and Results Atherosclerosis-prone apolipoprotein-E null (ApoE−/−) and TLR4 deficient (ApoE−/−TLR4−/−) mice were orally infected with the periodontal pathogen, Porphyromonas gingivalis. ApoE−/−TLR4−/− mice were markedly more susceptible to atherosclerosis following oral infection with P. gingivalis. Using live animal imaging, we demonstrate that enhanced lesion progression occurs progressively and was increasingly evident with advancing age. Immunohistochemical analysis of lesions from ApoE−/−TLR4−/− mice revealed an increased inflammatory cell infiltrate composed primarily of macrophages and IL-17 effector T cells (Th17), a subset linked with chronic inflammation. Furthermore, enhanced atherosclerosis in TLR4-deficient mice was associated with impaired development of T helper type-1 (Th1) immunity and regulatory T cell (Treg) infiltration. In vitro studies suggest that the mechanism of TLR4-mediated protective immunity may be orchestrated by dendritic cell interleukin (IL)-12 and IL-10, prototypic Th1 and Treg polarizing cytokines. Conclusions We demonstrate an atheroprotective role for TLR4 in response to infection with the oral pathogen, P. gingivalis. Our results point to a role for pathogen-specific TLR signaling in chronic inflammation and atherosclerosis.