Stefanie M. Brendecke

A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation

Microglia are brain macrophages and, as such, key immune-competent cells that can respond to environmental changes. Understanding the mechanisms of microglia-specific responses during pathologies is hence vital for reducing disease burden. The definition of microglial functions has so far been hampered by the lack of genetic in vivo approaches that allow discrimination of microglia from closely related peripheral macrophage populations in the body. Here we introduce a mouse experimental system that specifically targets microglia to examine the role of a mitogen-associated protein kinase kinase kinase (MAP3K), transforming growth factor (TGF)-β-activated kinase 1 (TAK1), during autoimmune inflammation. Conditional depletion of TAK1 in microglia only, not in neuroectodermal cells, suppressed disease, significantly reduced CNS inflammation and diminished axonal and myelin damage by cell-autonomous inhibition of the NF-κB, JNK and ERK1/2 pathways. Thus, we found TAK1 to be pivotal in CNS autoimmunity, and we present a tool for future investigations of microglial function in the CNS.

Complex Plaques in the Proximal Descending Aorta. An Underestimated Embolic Source of Stroke

Background and Purpose— To investigate the incidence of retrograde flow from complex plaques (≥4-mm-thick, ulcerated, or superimposed thrombi) of the descending aorta (DAo) and its potential role in embolic stroke. Methods— Ninety-four consecutive acute stroke patients with aortic plaques ≥3-mm-thick in transesophageal echocardiography were prospectively included. MRI was performed to localize complex plaques and to measure time-resolved 3-dimensional blood flow within the aorta. Three-dimensional visualization was used to evaluate if diastolic retrograde flow connected plaque location with the outlet of the left subclavian artery, left common carotid artery, or brachiocephalic trunk. Complex DAo plaques were considered an embolic source if retrograde flow reached a supra-aortic vessel that supplied the territory of visible acute and embolic retinal or cerebral infarction. Results— Only decreasing heart rate was correlated (P<0.02) with increasing flow reversal to the aortic arch. Retrograde flow from complex DAo plaques reached the left subclavian artery in 55 (58.5%), the left common carotid artery in 23 (24.5%), and the brachiocephalic trunk in 13 patients (13.8%). Based on routine diagnostics and MRI of the ascending aorta/aortic arch, stroke etiology was determined in 57 and cryptogenic in 37 patients. Potential embolization from DAo plaques was then identified in 19 of 57 patients (33.3%) with determined and in 9 of 37 patients (24.3%) with cryptogenic stroke. Conclusions— Retrograde flow from complex DAo plaques was frequent in both determined and cryptogenic stroke and could explain embolism to all brain territories. These findings suggest that complex DAo plaques should be considered a new source of stroke.

USP18 lack in microglia causes destructive interferonopathy of the mouse brain

Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called “microgliopathies”. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. Here, we identified the ubiquitin‐specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence. We further found that microglial Usp18 negatively regulates the activation of Stat1 and concomitant induction of interferon‐induced genes, thereby terminating IFN signaling. The Usp18‐mediated control was independent from its catalytic activity but instead required the interaction with Ifnar2. Additionally, the absence of Ifnar1 restored microglial activation, indicating a tonic IFN signal which needs to be negatively controlled by Usp18 under non‐diseased conditions. These results identify Usp18 as a critical negative regulator of microglia activation and demonstrate a protective role of Usp18 for microglia function by regulating the Ifnar pathway. The findings establish Usp18 as a new molecule preventing destructive microgliopathy.

Estimation of global aortic pulse wave velocity by flow-sensitive 4D MRI.

The aim of this study was to determine the value of flow‐sensitive four‐dimensional MRI for the assessment of pulse wave velocity as a measure of vessel compliance in the thoracic aorta. Findings in 12 young healthy volunteers were compared with those in 25 stroke patients with aortic atherosclerosis and an age‐matched normal control group (n = 9). Results from pulse wave velocity calculations incorporated velocity data from the entire aorta and were compared to those of standard methods based on flow waveforms at only two specific anatomic landmarks. Global aortic pulse wave velocity was higher in patients with atherosclerosis (7.03 ± 0.24 m/sec) compared to age‐matched controls (6.40 ± 0.32 m/sec). Both were significantly (P < 0.001) increased compared to younger volunteers (4.39 ± 0.32 m/sec). Global aortic pulse wave velocity in young volunteers was in good agreement with previously reported MRI studies and catheter measurements. Estimation of measurement inaccuracies and error propagation analysis demonstrated only minor uncertainties in measured flow waveforms and moderate relative errors below 16% for aortic compliance in all 46 subjects. These results demonstrate the feasibility of pulse wave velocity calculation based on four‐dimensional MRI data by exploiting its full volumetric coverage, which may also be an advantage over standard two‐dimensional techniques in the often‐distorted route of the aorta in patients with atherosclerosis. Magn Reson Med, 2010.

Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy.

Do not judge a cell by its cover—diversity of CNS resident, adjoining and infiltrating myeloid cells in inflammation

Specialized populations of tissue-resident myeloid cells inhabit every organ of the body. While many of these populations appear similar morphologically and phenotypically, they exhibit great functional diversity. The central nervous system (CNS), as an immune privileged organ, possesses a unique tissue-resident macrophage population, the microglia, as well as numerous myeloid cell subsets at its boarders and barriers in CNS-adjoining tissues, namely the meninges, the perivascular space, and the choroid plexus. Recent research has added much to our knowledge about microglia, whereas the populations of CNS-surrounding phagocytes are just starting to be appreciated. As guardians of CNS homeostasis, these myeloid cells perform immune surveillance and immune modulatory tasks in health and disease. As such, microglia and CNS-surrounding antigen-presenting cells have been shown to be crucially involved not only in the initiation and progression but also resolution of multiple sclerosis (MS). MS and its rodent model, experimental autoimmune encephalomyelitis, are autoimmune inflammatory demyelinating CNS pathologies. While some crucial aspects of the disease pathogenesis have been solved, much of the complex involvement and interplay of the innate immune compartment remains yet to be clarified. Here, we will discuss the current understanding of the scope of phenotypes and functions of myeloid cells involved in CNS neuroinflammation.

Co-registration of the distribution of wall shear stress and 140 complex plaques of the aorta☆

Previous studies provide evidence that atherosclerosis develops in vascular regions exposed to low wall shear stress (WSS) and high oscillatory shear index (OSI). 4D flow MRI was analyzed in 70 stroke patients with complex plaques (≥4 mm thickness, ulcerated or superimposed thrombi) and in 12 young healthy volunteers. The segmental distribution of peak systolic WSSsystole and OSI was quantified in analysis planes positioned directly at the location of 140 complex plaques found in the 70 patients. In addition, WSSsystole and OSI were evaluated in 8 standard analysis planes distributed along the aorta. Complex plaques were predominantly found at the inner curvature of the aortic arch and of the descending aorta. High OSI was co-located with the segments mostly affected by complex plaque while WSSsystole demonstrated a homogenous distribution. In standard analysis planes, patients demonstrated significantly (p<0.01) altered distribution of wall parameters compared to volunteers (reduced WSSsystole in 91% of aortic wall segments, increased OSI in 48% of segments). OSI distribution was asymmetric with higher values at the inner curvature of the aorta. While WSS and OSI showed expected changes in patients compared to healthy controls, their distribution pattern at complex plaques indicated a more complex and heterogeneous relationship than previously anticipated.

How type I interferons shape myeloid cell function in CNS autoimmunity

The precise mechanisms underlying the effects of IFN‐I in CNS autoimmunity remain poorly understood despite the long‐standing use of these cytokines as first‐line disease‐modifying drugs in the treatment of RRMS, a chronic demyelinating CNS autoimmune disease. Systemic use of IFN‐I results in pleiotropic immunomodulation linking the innate and adaptive immune responses. Recent research has demonstrated that in the setting of CNS autoimmunity, IFNs‐I have multiple effects on myeloid cell subsets, such as circulating monocytes, granulocytes, DCs, and tissue macrophages, such as microglia. These diverse effects include changes in cell activation, maturation, antigen presentation, and cytokine production, thus influencing T cell differentiation and expansion, as well as the regulation of executive functions, such as apoptosis and phagocytosis. Moreover, current data suggest that the engagement of the IFNAR on myeloid cells changes the activation status of the inflammasome in a cell type‐specific manner. Whereas most reports support primarily immune‐suppressive effects of IFN‐I on myeloid cells, endogenously produced, exogenously induced, and peripherally administered IFNs‐I exert complex differential spatial effects during CNS autoimmune inflammation. Clearly characterizing the molecular and cellular basis of these effects promises to yield viable targets for a more directed, localized, cell type‐specific IFN‐I‐based therapeutic approach. This kind of approach would allow for replacing the current treatment strategy in MS of broadly and unselectively altering all immune responses, regardless of their beneficial or detrimental nature.

3D MRI provides improved visualization and detection of aortic arch plaques compared to transesophageal echocardiography

To compare 3D magnetic resonance imaging (3D MRI) with transesophageal echocardiography (TEE) for the detection of complex aortic plaques (≥4 mm thick, ulcerated, or containing mobile thrombi).

Complex Plaques in the Proximal Descending Aorta: An Underestimated Embolic Source of Stroke * Supplemental Data - Video:

Background and Purpose— To investigate the incidence of retrograde flow from complex plaques (≥4-mm-thick, ulcerated, or superimposed thrombi) of the descending aorta (DAo) and its potential role in embolic stroke. Methods— Ninety-four consecutive acute stroke patients with aortic plaques ≥3-mm-thick in transesophageal echocardiography were prospectively included. MRI was performed to localize complex plaques and to measure time-resolved 3-dimensional blood flow within the aorta. Three-dimensional visualization was used to evaluate if diastolic retrograde flow connected plaque location with the outlet of the left subclavian artery, left common carotid artery, or brachiocephalic trunk. Complex DAo plaques were considered an embolic source if retrograde flow reached a supra-aortic vessel that supplied the territory of visible acute and embolic retinal or cerebral infarction. Results— Only decreasing heart rate was correlated (P<0.02) with increasing flow reversal to the aortic arch. Retrograde flow from complex DAo plaques reached the left subclavian artery in 55 (58.5%), the left common carotid artery in 23 (24.5%), and the brachiocephalic trunk in 13 patients (13.8%). Based on routine diagnostics and MRI of the ascending aorta/aortic arch, stroke etiology was determined in 57 and cryptogenic in 37 patients. Potential embolization from DAo plaques was then identified in 19 of 57 patients (33.3%) with determined and in 9 of 37 patients (24.3%) with cryptogenic stroke. Conclusions— Retrograde flow from complex DAo plaques was frequent in both determined and cryptogenic stroke and could explain embolism to all brain territories. These findings suggest that complex DAo plaques should be considered a new source of stroke.