The NKCC1 ion transporter modulates microglial phenotype and inflammatory response to brain injury in a cell-autonomous manner

The NKCC1 ion transporter contributes to the pathophysiology of common neurological disorders, but its function in microglia, the main inflammatory cells of the brain, has remained unclear to date. Therefore, we generated a novel transgenic mouse line in which microglial NKCC1 was deleted. We show that microglial NKCC1 shapes both baseline and reactive microglia morphology, process recruitment to the site of injury, and adaptation to changes in cellular volume in a cell-autonomous manner via regulating membrane conductance. In addition, microglial NKCC1 deficiency results in NLRP3 inflammasome priming and increased production of interleukin-1 beta (IL-1 beta), rendering microglia prone to exaggerated inflammatory responses. In line with this, central (intracortical) administration of the NKCC1 blocker, bumetanide, potentiated intracortical lipopolysaccharide (LPS)-induced cytokine levels. In contrast, systemic bumetanide application decreased inflammation in the brain. Microglial NKCC1 KO animals exposed to experimental stroke showed significantly increased brain injury, inflammation, cerebral edema, and, worse, neurological outcome. Thus, NKCC1 emerges as an important player in controlling microglial ion homeostasis and inflammatory responses through which microglia modulate brain injury. The contribution of microglia to central NKCC1 actions is likely to be relevant for common neurological disorders.Peer reviewe

Complement C5a inhibition improves late hemodynamic and inflammatory changes in a rat model of nonocclusive mesenteric ischemia

BACKGROUND: Nonocclusive mesenteric ischemia (NOMI) can evolve in a variety of low-flow states. Although the mechanisms leading to NOMI-related intestinal necrosis are largely unknown, circumstantial evidence suggests that excessive vasoconstriction and complement activation both play important roles in this process. Because targeting of the circulatory malfunction of the splanchnic area could be of therapeutic relevance, we set out to investigate the long-term effects of treatment with a complement C5a antagonist in a rat model of partial aortic occlusion (PAO)-induced transient mesenteric hypoperfusion. METHODS: The mean arterial pressure of the splanchnic area was kept between 30 and 40 mm Hg by 60 minutes of PAO in anesthetized male Sprague-Dawley rats. C5a inhibitor acetyl-peptide-A (AcPepA; 4 mg kg-1 intravenously) or vehicle administration was initiated at the 45th minute of PAO. After 24 hours, the animals were reanesthetized to record the macrohemodynamics and ileal microcirculation, and plasma and tissue samples were taken for determination of high-mobility group box protein-1 (HMGB-1), endothelin-1, tumor necrosis factor (TNF)-alpha levels, and small intestinal leukocyte infiltration. Epithelial structural changes were visualized by in vivo confocal laser scanning endomicroscopy. RESULTS: At 24 hours after PAO, mean arterial pressure, heart rate, and cardiac output were significantly greater, the intestinal intramural microcirculation was significantly impaired, and plasma HMGB-1, endothelin-1, TNF-alpha levels, the degree of epithelial damage and leukocyte infiltration was increased. The AcPepA treatment moderated the hemodynamic and microcirculatory changes, and decreased inflammatory activation and histologic signs of mucosal damage. CONCLUSION: C5a inhibition ameliorated the potentially harmful local mesenteric hypoperfusion and global long-term inflammatory consequences of PAO. This approach is of promise for use in NOMI-associated situations

A Zepetneki Tötösy család adattára / Records of the Tötösy de Zepetnek Family

A Zepetneki Tötösy család adattára/Records of the Tötösy de Zepetnek Family (Szeged: Attila József University, 1993. ISBN 9634819141 ©Steven Tötösy de Zepetnek https://docs.lib.purdue.edu/clcweblibrary/totosyrecords1993 ) contains transcripts of published data, archival and family documents, and genealogies of the Tötösy de Zepethnek family and its selected collateral families. A Zepetneki Tötösy család adattára includes data about other Töt(t)ös(s)(i)y families not related by origin to the Tötösy de Zepetnek family. The revised and updated version of the 1993 print book is Records of the Tötösy de Zepetnek Family/A Zepetneki Tötösy család adattára. West Lafayette: Purdue University Press, 2010-. ISSN 1715-152X https://docs.lib.purdue.edu/clcweblibrary/totosyrecords ©Steven Tötösy de Zepetnek & Purdue University Press. A Zepetneki Tötösy család adattára/Records of the Tötösy de Zepetnek Family (Szeged: Attila József University, 1993. ISBN 9634819141 ©Steven Tötösy de Zepetnek https://docs.lib.purdue.edu/clcweblibrary/totosyrecords1993 ) a család és szemelt rokon családainak nyomtatásban kiadott, levéltári és családi okmányait és családfáit tartalmazza. A Zepetneki Tötösy család adattára tartalmazza más Töt(t)ö(s)(i)y családok adatait melyek nem származásbeli rokonai a Zepetneki Tötösy családnak. Bővitett és javított verziója az 1993. kiadott könyvnek: Records of the Tötösy de Zepetnek Family/A Zepetneki Tötösy család adattára. West Lafayette: Purdue University Press, 2010-. ISSN 1715-152X https://docs.lib.purdue.edu/clcweblibrary/totosyrecords ©Steven Tötösy de Zepetnek & Purdue University Press