Sialyltransferase ST3Gal-IV controls CXCR2-mediated firm leukocyte arrest during inflammation

Recent in vitro studies have suggested a role for sialylation in chemokine receptor binding to its ligand (Bannert, N., S. Craig, M. Farzan, D. Sogah, N.V. Santo, H. Choe, and J. Sodroski. 2001. J. Exp. Med. 194:1661-1673). This prompted us to investigate chemokine-induced leukocyte adhesion in inflamed cremaster muscle venules of alpha2,3 sialyltransferase (ST3Gal-IV)-deficient mice. We found a marked reduction in leukocyte adhesion to inflamed microvessels upon injection of the CXCR2 ligands CXCL1 (keratinocyte-derived chemokine) or CXCL8 (interleukin 8). In addition, extravasation of ST3Gal-IV(-/-) neutrophils into thioglycollate-pretreated peritoneal cavities was significantly decreased. In vitro assays revealed that CXCL8 binding to isolated ST3Gal-IV(-/-) neutrophils was markedly impaired. Furthermore, CXCL1-mediated adhesion of ST3Gal-IV(-/-) leukocytes at physiological flow conditions, as well as transendothelial migration of ST3Gal-IV(-/-) leukocytes in response to CXCL1, was significantly reduced. In human neutrophils, enzymatic desialylation decreased binding of CXCR2 ligands to the neutrophil surface and diminished neutrophil degranulation in response to these chemokines. In addition, binding of alpha2,3-linked sialic acid-specific Maackia amurensis lectin II to purified CXCR2 from neuraminidase-treated CXCR2-transfected HEK293 cells was markedly impaired. Collectively, we provide substantial evidence that sialylation by ST3Gal-IV significantly contributes to CXCR2-mediated leukocyte adhesion during inflammation in vivo.     

Induction of autoimmune depression in mice by anti-ribosomal P antibodies via the limbic system

OBJECTIVE: Autoantibodies against ribosomal P proteins are linked to the neuropsychiatric manifestations of systemic lupus erythematosus (SLE). The present study was undertaken to assess how the specific brain-binding autoantibody anti-ribosomal P can induce a depression-type psychiatric disorder in mice. METHODS: Mice were injected intracerebroventricularly with affinity-purified human anti-ribosomal P antibodies or IgG as control. Pharmacologic and immunologic treatments included the antidepressant drug fluoxetine, the antipsychotic drug haloperidol, and antiidiotypic antibodies. Behavior was assessed by the forced swimming test, motor deficits by rotarod, grip strength, and staircase tests, and cognitive deficits by T-maze alternation and passive avoidance tests. RESULTS: Anti-ribosomal P antibodies induced depression-like behavior in the mice (mean +/- SEM 147.3 +/- 19.2 seconds of immobility versus 75.2 +/- 12.1 seconds of immobility in IgG-injected control mice; P < 0.005). The anti-ribosomal P antibody-induced depression-like behavior was partially blocked by a specific antiidiotypic antibody and significantly blocked by long-term treatment with fluoxetine, but not by short- or long-term treatment with haloperidol. The depressive behavior was not associated with any motor or cognitive deficits. Anti-ribosomal P antibodies specifically stained neurons in the hippocampus, cingulate cortex, and the primary olfactory piriform cortex, compatible with the previously described binding to the membrane-bound P0 ribosomal protein. CONCLUSION: This is the first report of an experimental depression induced by a specific autoantibody. The results implicate olfactory and limbic areas in the pathogenesis of depression in general, and in central nervous system dysfunction in SLE in particular.     

Bulbospinal neurons of the rat rostromedial medulla are highly collateralized

The rostromedial medulla participates in a large variety of sensory, motor, and autonomic functions. We asked whether individual bulbospinal neurons in this region have localized, target-specific terminal arbors or whether they collateralize broadly in the spinal cord. Collateralization was quantified along three spinal axes, rostrocaudal, left-right, and dorsoventral, by using double retrograde labeling. Fluorogold was applied to one target, and cholera toxin B chain (CTB) was applied to the second. We determined the prevalence of neurons that retrogradely label with both tracers in the constituent nuclei of the rostromedial medulla, the raphe nuclei, the gigantocellular reticular nucleus (Gi, bilaterally), the Gi pars alpha (GiA, bilaterally), and the midline medullary reticular formation. A large fraction of neurons in each of these nuclei had bulbospinal projections, ranging from > or =56% for the raphe nuclei to > or =14% for the Gi. For reasons discussed, these values are probably underestimates. Most of the neurons that projected to the lumbar spinal cord also projected to the cervical cord. Likewise, most neurons that projected to the ventral horn also had a collateral branch in the dorsal horn. However, relatively few had bilateral projections; most projected ipsilaterally or contralaterally. A considerable degree of collateralization was also seen among vestibulospinal neurons. The high level of collateralization of the descending projections of the rostromedial medulla suggests that neurons in this area ultimately act on peripheral target tissues or functions that are widely distributed in the body, or that they play a generalized modulatory role across functional modalities, rather than playing specific topographically delimited roles.     

Ectotherm mitochondrial economy and responses to global warming

Temperature is a key abiotic factor affecting ecology, biogeography, and evolution of species. Alterations of energy metabolism play an important role in adaptations and plastic responses to temperature shifts on different time scales. Mitochondrial metabolism affects cellular bioenergetics and redox balance making these organelles an important determinant of organismal performances such as growth, locomotion, or development. Here I analyze the impacts of environmental temperature on the mitochondrial functions (including oxidative phosphorylation, proton leak, production of reactive oxygen species(ROS), and ATP synthesis) of ectotherms and discuss the mechanisms underlying negative shifts in the mitochondrial energy economy caused by supraoptimal temperatures. Owing to the differences in the thermal sensitivity of different mitochondrial processes, elevated temperatures (beyond the species- and population-specific optimal range) cause reallocation of the electron flux and the protonmotive force (Δp) in a way that decreases ATP synthesis efficiency, elevates the relative cost of the mitochondrial maintenance, causes excessive production of ROS and raises energy cost for antioxidant defense. These shifts in the mitochondrial energy economy might have negative consequences for the organismal fitness traits such as the thermal tolerance or growth. Correlation between the thermal sensitivity indices of the mitochondria and the whole organism indicate that these traits experience similar selective pressures but further investigations are needed to establish whether there is a cause-effect relationship between the mitochondrial failure and loss of organismal performance during temperature change.     

Sepsis-associated encephalopathy: a magnetic resonance imaging and spectroscopy study

Brain dysfunction is frequently observed in sepsis as a consequence of changes in cerebral structure and metabolism, resulting in worse outcome and reduced life-quality of surviving patients. However, the mechanisms of sepsis-associated encephalopathy development and a better characterization of this syndrome in vivo are lacking. Here, we used magnetic resonance imaging (MRI) techniques to assess brain morphology and metabolism in a murine sepsis model (cecal ligation and puncture, CLP). Sham-operated and CLP mice were subjected to a complete MRI session at baseline, 6 and 24 h after surgery. Accumulation of vasogenic edematic fluid at the base of the brain was observed in T₂-weighted image at 6 and 24 h after CLP. Also, the water apparent diffusion coefficients in both hippocampus and cortex were decreased, suggesting a cytotoxic edema in brains of nonsurvival septic animals. Moreover, the N-acetylaspartate/choline ratio was reduced in brains of septic mice, indicating neuronal damage. In conclusion, noninvasive assessment by MRI allowed the identification of new aspects of brain damage in sepsis, including cytotoxic and vasogenic edema as well as neuronal damage. These findings highlight the potential applications of MRI techniques for the diagnostic and therapeutic studies in sepsis.