Involvement of the Macrophage Migration Inhibitory Factor (MIF) in Lipedema

Lipedema is a chronic disorder that mainly affects women. It is often misdiagnosed, and its etiology remains unknown. Recent research indicates an accumulation of macrophages and a shift in macrophage polarization in lipedema. One known protein superfamily that contributes to macrophage accumulation and polarization is the macrophage migration inhibitory factor (MIF) family. MIF-1 and MIF-2 are ubiquitously expressed and also regulate inflammatory processes in adipose tissue. In this study, the expression of MIF-1, MIF-2 and CD74-a common receptor for both cytokines-was analyzed in tissue samples of 11 lipedema and 11 BMI-matched, age-matched and anatomically matched control patients using qPCR and immunohistochemistry (IHC). The mRNA expression of MIF-1 (mean 1.256;SD 0.303;p = 0.0485) and CD74 (mean 1.514;SD 0.397;p = 0.0097) were significantly elevated in lipedema patients, while MIF-2 expression was unaffected (mean 1.004;SD 0.358;p = 0.9718). The IHC analysis corroborated the results for CD74 expression on a cellular level. In conclusion, our results provide first evidence for a potential involvement of the MIF family, presumably via the MIF-1-CD74 axis, in lipedema

Importancia de la reacción del suelo. Acidez: pH. Necesidad de cal.

Instituto de Orientación y Asistencia Técnica del Oest

Diversity and inter-connections in the CXCR4 chemokine receptor/ligand family: molecular perspectives

CXCR4 and its ligand CXCL12 mediate the homing of progenitor cells in the bone marrow and their recruitment to sites of injury, as well as affect processes such as cell arrest, survival, and angiogenesis. CXCL12 was long thought to be the sole CXCR4 ligand, but more recently the atypical chemokine macrophage migration inhibitory factor (MIF) was identified as an alternative, non cognate ligand for CXCR4 and shown to mediate chemotaxis and arrest of CXCR4-expressing T-cells. This has complicated the understanding of CXCR4-mediated signaling and associated biological processes. Compared to CXCL12/CXCR4-induced signaling, only few details are known on MIF/CXCR4-mediated signaling and it remains unclear to which extent MIF and CXCL12 reciprocally influence CXCR4 binding and signaling. Furthermore, the atypical chemokine receptor 3 (ACKR3) (previously CXCR7) has added to the complexity of CXCR4 signaling due to its ability to bind CXCL12 and MIF, and to evoke CXCL12-and MIF-triggered signaling independently of CXCR4. Also, extracellular ubiquitin (eUb) and the viral protein gp120 (HIV) have been reported as CXCR4 ligands, whereas viral chemokine vMIP-11 (Herpesvirus) and human beta 3-defensin (HBD-3) have been identified as CXCR4 antagonists. This review will provide insight into the diversity and inter-connections in the CXCR4 receptor/ligand family. We will discuss signaling pathways initiated by binding of CXCL12 vs. MIF to CXCR4, elaborate on how ACKR3 affects CXCR4 signaling, and summarize biological functions of CXCR4 signaling mediated by CXCL12 or MIF. Also, we will discuss eUb and gp120 as alternative ligands for CXCR4, and describe vMIP-11 and HBD-3 as antagonists for CXCR4. Detailed insight into biological effects of CXCR4 signaling und underlying mechanisms, including diversity of CXCR4 ligands and inter connections with other (chemokine) receptors, is clinically important, as the CXCR4 antagonist AMD3100 has been approved as stem cell mobilizer in specific disease settings

Differential Role for Activating Fc gamma RIII in Neointima Formation After Arterial Injury and Diet-Induced Chronic Atherosclerosis inApolipoprotein E-Deficient Mice

Atherogenesis and arterial remodeling following mechanical injury are driven by inflammation and mononuclear cell infiltration. The binding of immune complexes (ICs) to immunoglobulin (Ig)-Fc gamma receptors (Fc gamma Rs) on most innate and adaptive immune cells induces a variety of inflammatory responses that promote atherogenesis. Here, we studied the role of Fc gamma RIII in neointima formation after arterial injury in atherosclerosis-prone mice and compared the outcome and mechanism to that of Fc gamma RIII in diet-induced chronic atherosclerosis.Fc gamma rIII(-/-)/Apoe(-/-)and controlApoe(-/-)mice were subjected to wire-induced endothelial denudation of the carotid artery while on high-fat diet (HFD).Fc gamma rIIIdeficiency mitigated neointimal plaque formation and lesional macrophage accumulation, and enhanced neointimal vascular smooth muscle cell (VSMC) numbers. This went along with a reduced expression of tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1/CCL2), and vascular cell adhesion molecule-1 (VCAM-1) in the neointimal lesions. Interestingly, in a chronic model of diet-induced atherosclerosis, we unraveled a dichotomic role of Fc gamma RIII in an early versus advanced stage of the disease. WhileFc gamma rIIIdeficiency conferred atheroprotection in the early stage, it promoted atherosclerosis in advanced stages. To this end,Fc gamma rIIIdeficiency attenuated pro-inflammatory responses in early atherosclerosis but promoted these events in advanced stages. Analysis of the mechanism(s) underlying the athero-promoting effect ofFc gamma rIIIdeficiency in late-stage atherosclerosis revealed increased serum levels of anti-oxidized-LDL immunoglobulins IgG2c and IgG2b. This was paralleled by enhanced lesional accumulation of IgGs without affecting levels of complement-activated products C5a or C5ar1, Fc gamma RII, and Fc gamma RIV. Moreover,Fc gamma rIII-deficient macrophages expressed moreFc gamma rII,Tnf-alpha, andIl-1 beta mRNA when exposed to IgG1 or oxLDL-IgG1 ICsin vitro, and peripheral CD4+ and CD8+ T-cell levels were altered. Collectively, our data suggest that deficiency of activatingFc gamma RIIIlimits neointima formation after arterial injury in atherosclerosis-prone mice as well as early stage chronic atherosclerosis, but augments late-stage atherosclerosis suggesting a dual role of Fc gamma RIII in atherogenic inflammation

Mastoidrekonstruktion mit einem Titangitter

Einleitung: Bei der Cholesteatomsanierung hat sich die am Entstehungsweg orientierende Operationsmethode bewährt. Dabei wird das Cholesteatom vom Entstehungsort unter Abfräsen der hinteren Gehörgangswand und des lateralen Mastoids freigelegt. Zur Wiederherstellung ursprünglicher Verhältnisse ist die Rekonstruktion der hinteren Gehörgangswand angezeigt. Knorpel allein erweist sich häufig als zu wenig resistent. Alle bisherigen Methoden der Rekonstruktion haben sich rein auf die Hinterwand beschränkt. Das hier vorgestellte Verfahren zielt auf eine gesamte Rekonstruktion des Mastoids einschließlich septaler Strukturen ab. Methode: 10 Patienten, bei denen eine Mastoidrekonstruktion mit Titan-Gitter vorgenommen wurde, konnten ausgewertet werden. Das Gitter wurde derart gestaltet, dass nicht nur die Gehörgangshinterwand sondern auch das Trabekelsystem des Mastoids nachgebildet wurde. Die Bedeckung erfolgte mit Knorpel. Ergebnisse: Bei allen Patienten kam es zu einer regelhaften Abheilung des Gehörgangs. Der Knorpel heilte problemlos ein mit vollständiger Epithelisierung, freiliegendes Implantatmaterial wurde in keinem Fall beobachtet. Die durchschnittliche Nachbeobachtungszeit beträgt derzeit 17,75 Monate (minimal 9 Monate, maximal 26 Monate).Schlussfolgerung: Die Methode der Mastoidrekonstruktion scheint gegenüber der reinen Rekonstruktion der Hinterwand, die meist mit Verschraubungen vorgenommen wurden, deutliche Vorteile zu haben. Eine bessere Bedeckung mit Knorpel und die abstützende Funktion des Trabekelwerkes scheint hier wesentlich zu sein, wobei die bekannte Mittelohrkompatibiliät von Titan sicher mitentscheidend ist

Converting cold into pain

Cold temperature can evoke a wide spectrum of perceptual sensations that range from freshness to unpleasant cold or overt pain. In mammals, the detection of cold temperature is accomplished by the activation of different subsets of sensory terminals innervating the skin and mucosae. Direct recordings of corneal nerve endings, combined with studies of thermoreceptive neurons in culture, have allowed the characterization of ionic mechanisms involved in cold temperature sensing. In recent years, major progress has also taken place in the identification and operation of thermally gated ion channels, especially of the transient receptor potential (TRP) family. However, it is still uncertain how individual sensory endings can be activated with different thermal thresholds. In this review, we have considered the known properties of cold-sensitive receptors and their transduction mechanisms and related them to the sensations they evoke. We analyzed the evidence linking specific ion channels to the activation of particular sets of afferent fibers. In our view, cold thermotransduction is complex and involves the concerted operation of several ion channels. Excitatory effects of cationic channels (e.g., TRPs) balance their activity with several excitability brakes (e.g., potassium channels), leading to tunable levels of sensory thresholds and activity. Alteration in this fine balance may result in altered cold sensitivity, a frequent symptom in patients with peripheral nerve injury. © 2009 Springer-Verlag.We would also like to acknowledge the funding from the Spanish MICINN (projects BFU2007-61855, BFU2008-04425 and CONSOLIDER-INGENIO 2010 CSD2007-0002) and from the Fundación Marcelino Botín.Peer Reviewe

Endothelial CSN5 impairs NF-kappa B activation and Monocyte adhesion to endothelial cells and is highly expressed in human atherosclerotic lesions

The COP9 signalosome (CSN), a multifunctional protein complex involved in the regulation of cullin-RING-E3 ubiquitin ligases (CRLs), has emerged as a regulator of NF-kappa B signalling. As NE-kappa B drives the expression of pro-inflammatory and pro-atherosclerotic genes, we probed the yet unknown role of the CSN, in particular CSN5, on NF-kappa B-mediated atherogenic responses in endothelial cells. Co-immunoprecipitation in human umbilical vein endothelial cells (HUVECs) revealed the presence of a super-complex between IKK and CSN, which dissociates upon TNF-alpha stimulation. Furthermore, CSN5 silencing enhanced TNF-alpha-induced IKB-alpha degradation and NF-kappa B activity in luciferase reporter assays. This was paralleled by an increased NF-kappa B-driven upregulation of atherogenic chemokines and adhesion molecules, as measured by qPCR and flow cytometry, and translated into an enhanced arrest of THP-1 monocytes on TNF-alpha-stimulated, CSN5-depleted HUVECs. Reverse effects on NF-kappa B activity and THP-1 arrest were seen upon CSN5 overexpression. Finally, double-immunostaining confirmed the expression of CSN subunits in the endothelium of human atherosclerotic lesions, and revealed an increased expression of CSN5 which correlated with atheroprogression. In conclusion, endothelial CSN5 attenuates NF-kappa B-dependent pro-inflammatory gene expression and monocyte arrest on stimulated endothelial cells in vitro, suggesting that CSN5 might serve as a negative regulator of atherogenesis

MIF but not MIF-2 recruits inflammatory macrophages in an experimental polymicrobial sepsis model

Excessive inflammation drives the progression from sepsis to septic shock. Macrophage migration inhibitory factor (MIF) is of interest because MIF promoter polymorphisms predict mortality in different infections, and anti-MIF antibody improves survival in experimental models when administered 8 hours after infectious insult. The recent description of a second MIF superfamily member, D-dopachrometautomerase (D-DT/MIF-2), prompted closer investigation of MIF-dependent responses. We subjected Mif(-/-) and Mif-2(-/-) mice to polymicrobial sepsis and observed a survival benefit with Mif but not Mif-2 deficiency. Survival was associated with reduced numbers of small peritoneal macrophages (SPMs) that, in contrast to large peritoneal macrophages (LPMs), were recruited into the peritoneal cavity. LPMs produced higher quantities of MIF than SPMs, but SPMs expressed higher levels of inflammatory cytokines and the MIF receptors CD74 and CXCR2. Adoptive transfer of WT SPMs into Mif(-/-) hosts reduced the protective effect of Mif deficiency in polymicrobial sepsis. Notably, MIF-2 lacks the pseudo-(E) LR motif present in MIF that mediates CXCR2 engagement and SPM migration, supporting a specific role for MIF in the recruitment and accumulation of inflammatory SPMs