Retinoic acid controls the homeostasis of pre-cDC–derived splenic and intestinal dendritic cells

Dendritic cells (DCs) comprise distinct populations with specialized immune-regulatory functions. However, the environmental factors that determine the differentiation of these subsets remain poorly defined. Here, we report that retinoic acid (RA), a vitamin A derivative, controls the homeostasis of pre-DC (precursor of DC)–derived splenic CD11b(+)CD8α(−)Esam(high) DCs and the developmentally related CD11b(+)CD103(+) subset within the gut. Whereas mice deprived of RA signaling significantly lost both of these populations, neither pre-DC–derived CD11b(−)CD8α(+) and CD11b(−)CD103(+) nor monocyte-derived CD11b(+)CD8α(−)Esam(low) or CD11b(+)CD103(−) DC populations were deficient. In fate-tracking experiments, transfer of pre-DCs into RA-supplemented hosts resulted in near complete conversion of these cells into the CD11b(+)CD8α(−) subset, whereas transfer into vitamin A–deficient (VAD) hosts caused diversion to the CD11b(−)CD8α(+) lineage. As vitamin A is an essential nutrient, we evaluated retinoid levels in mice and humans after radiation-induced mucosal injury and found this conditioning led to an acute VAD state. Consequently, radiation led to a selective loss of both RA-dependent DC subsets and impaired class II–restricted auto and antitumor immunity that could be rescued by supplemental RA. These findings establish a critical role for RA in regulating the homeostasis of pre-DC–derived DC subsets and have implications for the management of patients with immune deficiencies resulting from malnutrition and irradiation

Acquired von Willebrand syndrome in cardiogenic shock patients on mechanical circulatory microaxial pump support

<div><p>Early use of mechanical circulatory support, e.g. veno-arterial extracorporeal membrane oxygenation (ECMO) or left ventricular unloading by microaxial pump in refractory cardiogenic shock is recommended in current guidelines. Development of acquired von Willebrand Syndrome (AVWS) in patients with left ventricular assist devices (LVADs) and ECMO has been reported. There is an increasing number of patients treated with the Impella^® CP microaxial pump for left ventricular unloading. However, the prevalence of AVWS in these high risk patients is unknown and needs to be determined. We therefore screened 21 patients (68 ± 11years) treated with Impella^® (17 for cardiogenic shock, 4 for protected PCI) for the presence of AVWS by determining von Willebrand factor multimers, VWF collagen binding capacity and VWF antigen. During the time course of Impella^® support, 20/21 patients (95%) developed AVWS (mean duration of support: 135 ± 114 hours, mean time from device implantation to first diagnosis of AVWS: 10.6 ± 10.8 hours). Our data indicate that AVWS is a common phenomenon during left ventricular unloading via microaxial pump support. Thus, AVWS has to be considered as contributing factor for potential bleeding complications in this high risk patient population, especially in the context of dual antiplatelet therapy.</p></div

Course of VWF:CB / VWF:Ag ratio.

<p>Significant reduction of VWF:CB / VWF:Ag ratio during Impella^® support—and normalization after cessation of left ventricular unloading. n = 12, *p<0.05 vs pre / post Impella^® therapy.</p

Diagnostics of von Willebrand syndrome.

<p>Diagnostics of von Willebrand syndrome.</p

Patient characteristics.

<p>Patient characteristics.</p

Representative electrophoresis.

<p>Low-resolution gel (1.2%) of plasma from a patient with Impella^® support (marked lane) compared to other plasma samples. Very large VWF multimers are missing, large multimers are reduced.</p

Characteristic electrophoresis at different time points.

<p>Characteristic low-resolution gel (1.2%) of a patient with Impella^®: Very large multimers are absent and large multimes are reduced during microaxial pump support. Existence / recovery of large multimers is documented before and after mechanical left ventricular unloading. The right lane illustrates a characteristic trace of a plasma sample from a healthy person.</p

VASP regulates leukocyte infiltration, polarization, and vascular repair after ischemia

In ischemic vascular diseases, leukocyte recruitment and polarization are crucial for revascularization and tissue repair. We investigated the role of vasodilator-stimulated phosphoprotein (VASP) in vascular repair. After hindlimb ischemia induction, blood flow recovery, angiogenesis, arteriogenesis, and leukocyte infiltration into ischemic muscles in VASP−/− mice were accelerated. VASP deficiency also elevated the polarization of the macrophages through increased signal transducer and activator of transcription (STAT) signaling, which augmented the release of chemokines, cytokines, and growth factors to promote leukocyte recruitment and vascular repair. Importantly, VASP deletion in bone marrow–derived cells was sufficient to mimic the increased blood flow recovery of global VASP−/− mice. In chemotaxis experiments, VASP−/− neutrophils/monocytes were significantly more responsive to M1-related chemokines than wild-type controls. Mechanistically, VASP formed complexes with the chemokine receptor CCR2 and β-arrestin-2, and CCR2 receptor internalization was significantly reduced in VASP−/− leukocytes. Our data indicate that VASP is a major regulator of leukocyte recruitment and polarization in postischemic revascularization and support a novel role of VASP in chemokine receptor trafficking