Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor (CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1-/- mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1-/- mice showed more extensive neuronal cell loss than Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.

Phagocytic monocyte-derived macrophages associate with the nodes of Ranvier and initiate demyelination while microglia clear debris and display a suppressed metabolic gene signature in EAE.

Objective To determine the pathologic basis of subtle abnormalities in magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) parameters observed in normal-appearing white matter (NAWM) in multiple sclerosis (MS) brains. Methods Brain tissues were obtained through a rapid post-mortem protocol that included in situ MRI. Four types of MRI-defined regions of interest (ROIs) were analyzed: (1) Regions that were abnormal on all images (“T2T1MTR lesions”); (2) NAWM regions with slightly-abnormal MTR located close to white matter lesions (“sa-WM Close”); (3) NAWM regions with slightly-abnormal MTR located far from lesions (“sa-WM Far”); and (4) NAWM regions with normal MTR (“NAWM”). Immunohistochemical analysis for each ROI comprised immunostaining for myelin, axonal markers, activated microglia/macrophages, astrocytes, plasma proteins and blood vessels. Results Forty-eight ROIs from four secondary progressive MS brains were analyzed. Sa-WM Close ROIs were associated with significantly more axonal swellings. There were more enlarged MHCII(+) microglia and macrophages detected in sa-WM Far, sa-WM Close, and T2T1MTR lesions than in NAWM. Across all ROIs, MTR and DTI measures were moderately correlated with myelin density, axonal area and axonal counts. Excluding T2T1MTR lesions from analysis revealed that MTR and DTI measures in non-lesional WM were correlated with activated microglia, but not with axonal or myelin integrity. Interpretation The pathologic substrates for MRI abnormalities in NAWM vary based on distance from focal WM lesions. Close to WM lesions, axonal pathology and microglial activation may explain subtle MRI changes. Distant from lesions, microglial activation associated with proximity to cortical lesions might underlie MRI abnormalities.

Rationale: Pulmonary lymphangioleiomyomatosis is a progressive cystic lung disease that is associated with infiltration of atypical smooth muscle-like cells. Previous descriptions of clinical characteristics of subjects with lymphangioleiomyomatosis have been based on a limited number of patients. Objectives: To describe the clinical characteristics of subjects with pulmonary lymphangioleiomyomatosis, both sporadic and tuberous sclerosis-related forms. Methods: Over a 3-yr period, from 1998 to 2001, 243 subjects with pulmonary lymphangioleiomyomatosis were enrolled into a national registry; 13 subjects who had already undergone lung transplantation were excluded for the purposes of this report. Measurements and Main Results: All 230 subjects were women, aged 18 to 76 yr (mean Ϯ SE, 44.5 Ϯ 0.65 yr). The average age at onset of symptoms was 38.9 Ϯ 0.73 yr and at diagnosis was 41.0 Ϯ 0.65 yr. Tuberous sclerosis complex was present in 14.8% of subjects. Pulmonary manifestations, most commonly spontaneous pneumothorax, were the primary events leading to the diagnosis in 86.5% of cases. Nearly 55% of the subjects were being treated with a progesterone derivative. An obstructive pattern on pulmonary function testing was observed in 57.3% of the subjects, whereas 33.9% had normal spirometric results. Women with tuberous sclerosis-related lymphangioleiomyomatosis were younger and had less impaired lung function compared with those with the sporadic form. Conclusions: The age range of women afflicted with pulmonary lymphangioleiomyomatosis is broader than previously appreciated and the degree of pulmonary function can be quite variable, with one-third of subjects having normal spirometry at enrollment into this registry.