ABSTRACT
Cellular senescence is a hallmark of advanced age and a major instigator of numerous inflammatory pathologies. While endothelial cell (EC) senescence is aligned with defective vascular functionality, its impact on fundamental inflammatory responses in vivo at single-cell level remain unclear. To directly investigate the role of EC senescence on dynamics of neutrophil-venular wall interactions, we applied high resolution confocal intravital microscopy to inflamed tissues of an EC-specific progeroid mouse model, characterized by profound indicators of EC senescence. Progerin-expressing ECs supported prolonged neutrophil adhesion and crawling in a cell autonomous manner that additionally mediated neutrophil-dependent microvascular leakage. Transcriptomic and immunofluorescence analysis of inflamed tissues identified elevated levels of EC CXCL1 on progerin-expressing ECs and functional blockade of CXCL1 suppressed the dysregulated neutrophil responses elicited by senescent ECs. Similarly, cultured progerin-expressing human ECs exhibited a senescent phenotype, were pro-inflammatory and prompted increased neutrophil attachment and activation. Collectively, our findings support the concept that senescent ECs drive excessive inflammation and provide new insights into the mode, dynamics, and mechanisms of this response at single-cell level.
ABSTRACT
Chronic meningitis is a frequent disease; it constitutes a real diagnostic challenge because of different etiologic possibilities, the most important being infectious, chemical, inflammatory, tumoral, autoimmune and of unknown origin. Chronic meningitis, as a rule, needs the use of a wide and expensive battery of studies, but frequently despite all this, it is not possible to make a diagnosis. Biopsies of meninges and brain play a key role in the study of this type of patients. We present five cases of chronic meningitis; some important considerations are made in relation to diagnosis and therapeutic management.