1,421 research outputs found
Antitumor activity of an Artemisia annua herbal preparation and identification of active ingredients
Extracellular Vesicles in Musculoskeletal Pathologies and Regeneration
The incidence of musculoskeletal diseases is steadily increasing with aging of the population. In the past years, extracellular vesicles (EVs) have gained attention in musculoskeletal research. EVs have been associated with various musculoskeletal pathologies as well as suggested as treatment option. EVs play a pivotal role in communication between cells and their environment. Thereby, the EV cargo is highly dependent on their cellular origin. In this review, we summarize putative mechanisms by which EVs can contribute to musculoskeletal tissue homeostasis, regeneration and disease, in particular matrix remodeling and mineralization, pro-angiogenic effects and immunomodulatory activities. Mesenchymal stromal cells (MSCs) present the most frequently used cell source for EV generation for musculoskeletal applications, and herein we discuss how the MSC phenotype can influence the cargo and thus the regenerative potential of EVs. Induced pluripotent stem cell-derived mesenchymal progenitor cells (iMPs) may overcome current limitations of MSCs, and iMP-derived EVs are discussed as an alternative strategy. In the last part of the article, we focus on therapeutic applications of EVs and discuss both practical considerations for EV production and the current state of EV-based therapies
IRF4 and BATF are critical for CD8(+) T-cell function following infection with LCMV.
CD8(+) T-cell functions are critical for preventing chronic viral infections by eliminating infected cells. For healthy immune responses, beneficial destruction of infected cells must be balanced against immunopathology resulting from collateral damage to tissues. These processes are regulated by factors controlling CD8(+) T-cell function, which are still incompletely understood. Here, we show that the interferon regulatory factor 4 (IRF4) and its cooperating binding partner B-cell-activating transcription factor (BATF) are necessary for sustained CD8(+) T-cell effector function. Although Irf4(-/-) CD8(+) T cells were initially capable of proliferation, IRF4 deficiency resulted in limited CD8(+) T-cell responses after infection with the lymphocytic choriomeningitis virus. Consequently, Irf4(-/-) mice established chronic infections, but were protected from fatal immunopathology. Absence of BATF also resulted in reduced CD8(+) T-cell function, limited immunopathology, and promotion of viral persistence. These data identify the transcription factors IRF4 and BATF as major regulators of antiviral cytotoxic T-cell immunity
Adverse functions of ILā17A in experimental sepsis
ILā17A is a proinflammatory cytokine produced by a variety of cells. In the current study, we examined the role of ILā17A in sepsis induced in mice by cecal ligation and puncture (CLP). ILā17A levels, which rose timeādependently in plasma after CLP, were not affected in the absence of Ī±Ī² T cells or neutrophils. In sharp contrast, Ī³Ī“ T cellāknockout or Ī³Ī“ T cellādepleted mice displayed baseline ILā17A plasma levels after CLP. Neutralization of ILā17A by two different antibodies improved sepsis (survival from ~10% to nearly 60%). Unexpectedly, antibody treatment was protective, even when administration of antiāILā17A was delayed for up to 12 h after CLP. These protective effects of ILā17A blockade were associated with substantially reduced levels of bacteremia together with significant reductions of systemic proinflammatory cytokines and chemokines in plasma. In vitro incubation of mouse peritoneal macrophages with lipopolysaccharide (LPS) in the copresence of ILā17A substantially increased the production of TNFāĪ±, ILā1Ī², and ILā6 by these cells. These data suggest that, during experimental sepsis, Ī³Ī“ T cellāderived ILā17A promotes high levels of proinflammatory mediators and bacteremia, resulting in enhanced lethality. ILā17A may be a potential therapeutic target in sepsis.āFlierl, M. A., Rittirsch, D., Gao, H., Hoesel, L. M., Nadeau, B. A., Day, D. E., Zetoune, F. S., Sarma, J. V., HuberāLang, M. S., Ferrara, J. L. M., Ward, P. A. Adverse functions of ILā17A in experimental sepsis. FASEB J. 22, 2198ā2205 (2008)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154352/1/fsb2fj07105221.pd
Cross-Talk between TLR4 and FcĪ³ReceptorIII (CD16) Pathways
Pathogen-pattern-recognition by Toll-like receptors (TLRs) and pathogen clearance after immune complex formation via engagement with Fc receptors (FcRs) represent central mechanisms that trigger the immune and inflammatory responses. In the present study, a linkage between TLR4 and FcĪ³R was evaluated in vitro and in vivo. Most strikingly, in vitro activation of phagocytes by IgG immune complexes (IgGIC) resulted in an association of TLR4 with FcĪ³RIII (CD16) based on co-immunoprecipitation analyses. Neutrophils and macrophages from TLR4 mutant (mut) mice were unresponsive to either lipopolysaccharide (LPS) or IgGIC in vitro, as determined by cytokine production. This phenomenon was accompanied by the inability to phosphorylate tyrosine residues within immunoreceptor tyrosine-based activation motifs (ITAMs) of the FcRĪ³-subunit. To transfer these findings in vivo, two different models of acute lung injury (ALI) induced by intratracheal administration of either LPS or IgGIC were employed. As expected, LPS-induced ALI was abolished in TLR4 mut and TLR4ā/ā mice. Unexpectedly, TLR4 mut and TLR4ā/ā mice were also resistant to development of ALI following IgGIC deposition in the lungs. In conclusion, our findings suggest that TLR4 and FcĪ³RIII pathways are structurally and functionally connected at the receptor level and that TLR4 is indispensable for FcĪ³RIII signaling via FcRĪ³-subunit activation
The Complement Anaphylatoxin C5a Induces Apoptosis in Adrenomedullary Cells during Experimental Sepsis
Sepsis remains a poorly understood, enigmatic disease. One of the cascades crucially involved in its pathogenesis is the complement system. Especially the anaphylatoxin C5a has been shown to have numerous harmful effects during sepsis. We have investigated the impact of high levels of C5a on the adrenal medulla following cecal ligation and puncture (CLP)-induced sepsis in rats as well as the role of C5a on catecholamine production from pheochromocytoma-derived PC12 cells. There was significant apoptosis of adrenal medulla cells in rats 24 hrs after CLP, as assessed by the TUNEL technique. These effects could be reversed by dual-blockade of the C5a receptors, C5aR and C5L2. When rats were subjected to CLP, levels of C5a and norepinephrine were found to be antipodal as a function of time. PC12 cell production of norepinephrine and dopamine was significantly blunted following exposure to recombinant rat C5a in a time-dependent and dose-dependent manner. This impaired production could be related to C5a-induced initiation of apoptosis as defined by binding of Annexin V and Propidium Iodine to PC12 cells. Collectively, we describe a C5a-dependent induction of apoptotic events in cells of adrenal medulla in vivo and pheochromocytoma PC12 cells in vitro. These data suggest that experimental sepsis induces apoptosis of adrenomedullary cells, which are responsible for the bulk of endogenous catecholamines. Septic shock may be linked to these events. Since blockade of both C5a receptors virtually abolished adrenomedullary apoptosis in vivo, C5aR and C5L2 become promising targets with implications on future complement-blocking strategies in the clinical setting of sepsis
Agonists of proteinase-activated receptor-2 affect transendothelial migration and apoptosis of human neutrophils
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73837/1/j.1600-0625.2007.00605.x.pd
Accelerated apoptotic death and <i>in vivo</i> turnover of erythrocytes in mice lacking functional mitogen- and stress-activated kinase MSK1/2
The mitogen- and stress-activated kinase MSK1/2 plays a decisive role in
apoptosis. In analogy to apoptosis of nucleated cells, suicidal erythrocyte
death called eryptosis is characterized by cell shrinkage and cell membrane
scrambling leading to phosphatidylserine (PS) externalization. Here, we
explored whether MSK1/2 participates in the regulation of eryptosis. To this
end, erythrocytes were isolated from mice lacking functional MSK1/2 (mskā/ā)
and corresponding wild-type mice (msk+/+). Blood count, hematocrit, hemoglobin
concentration and mean erythrocyte volume were similar in both mskā/ā and
msk+/+ mice, but reticulocyte count was significantly increased in mskā/ā
mice. Cell membrane PS exposure was similar in untreated mskā/ā and msk+/+
erythrocytes, but was enhanced by pathophysiological cell stressors ex vivo
such as hyperosmotic shock or energy depletion to significantly higher levels
in mskā/ā erythrocytes than in msk+/+ erythrocytes. Cell shrinkage following
hyperosmotic shock and energy depletion, as well as hemolysis following
decrease of extracellular osmolarity was more pronounced in mskā/ā
erythrocytes. The in vivo clearance of autologously-infused CFSE-labeled
erythrocytes from circulating blood was faster in mskā/ā mice. The spleens
from mskā/ā mice contained a significantly greater number of PS-exposing
erythrocytes than spleens from msk+/+ mice. The present observations point to
accelerated eryptosis and subsequent clearance of erythrocytes leading to
enhanced erythrocyte turnover in MSK1/2-deficient mice
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