Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming

Human mesenchymal stromal cells (MSC) have been shown to dampen immune response and promote tissue repair, but the underlying mechanisms are still under investigation. Herein, we demonstrate that umbilical cord-derived MSC (UC-MSC) alter the phenotype and function of monocyte-derived dendritic cells (DC) through lactate-mediated metabolic reprogramming. UC-MSC can secrete large quantities of lactate and, when present during monocyte-to-DC differentiation, induce instead the acquisition of M2-macrophage features in terms of morphology, surface markers, migratory properties and antigen presentation capacity. Microarray expression profiling indicates that UC-MSC modify the expression of metabolic-related genes and induce a M2-macrophage expression signature. Importantly, monocyte-derived DC obtained in presence of UC-MSC, polarize naïve allogeneic CD4+ T-cells into Th2 cells. Treatment of UC-MSC with an inhibitor of lactate dehydrogenase strongly decreases lactate concentration in culture supernatant and abrogates the effect on monocyte-to- DC differentiation. Metabolic analysis further revealed that UC-MSC decrease oxidative phosphorylation in differentiating monocytes while strongly increasing the spare respiratory capacity proportional to the amount of secreted lactate. Because both MSC and monocytes are recruited in vivo at the site of tissue damage and inflammation, we propose the local increase of lactate concentration induced by UC-MSC and the consequent enrichment in M2-macrophage generation as a mechanism to achieve immunomodulation

Author Correction: Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial (Nature Medicine, (2021), 27, 11, (2012-2024), 10.1038/s41591-021-01488-2)

In the version of this Article initially published, there was an omission in the member list for the CONCOR-1 Study Group. Valérie Arsenault (Héma-Québec, Montreal, Quebec, Canada) has now been included in the CONCOR-1 Study Group in the online version of the article

Aβ pathology

IVIg protects the 3xTg-AD mouse model of Alzheimer’s disease from memory deficit an

Blood Endothelial-Cell Extracellular Vesicles as Potential Biomarkers for the Selection of Plasma in COVID-19 Convalescent Plasma Therapy

Despite the advancement of vaccination and therapies currently available, deaths due to the coronavirus disease 2019 (COVID-19) are still heavily documented. Severely infected individuals experience a generalized inflammatory storm, caused by massive secretion of pro-inflammatory cytokines that can lead to endothelial dysfunction, cardiovascular disease, multi-organ failure, and even death. COVID-19 convalescent plasma (CCP) therapy, selected primarily based on anti-SARS-CoV-2 antibody levels, has not been as convincing as expected in the fight against COVID-19. Given the consequences of a dysfunctional endothelium on the progression of the disease, we propose that the selection of plasma for CCP therapy should be based on more specific parameters that take into consideration the effect on vascular inflammation. Thus, in the present study, we have characterized a subset of CCP that have been used for CCP therapy and measured their anti- or pro-inflammatory effect on human coronary artery endothelial cells (HCAECs). Our data revealed that the longer the time lapse between the onset of symptoms and the plasma donation, the more mitochondrial dysfunction can be evidenced. The concentration of blood endothelial cell extracellular vesicles (BEC-EVs) was increased in the plasma of young individuals with mild symptoms. This type of selected convalescent plasma promoted the activation of the blood vascular endothelium, as reflected by the overexpression of ICAM1 and NFκB1 and the downregulation of VE-Cadherin. We propose this mechanism is a warning signal sent by the injured endothelium to trigger self-defense of peripheral blood vessels against excessive inflammation. Therefore, these results are in line with our previous data. They suggest that a more specific selection of COVID-19 convalescent plasma should be based on the time of donation following the onset of the clinical symptoms of the donor, the severity of the symptoms, and the age of the donor. These characteristics are relatively easy to identify in any hospital and would reflect the concentration of plasma BEC-EVs and be optimal in CCP therapy

Use of Early Donated COVID-19 Convalescent Plasma Is Optimal to Preserve the Integrity of Lymphatic Endothelial Cells

Convalescent plasma therapy (CPT) has gained significant attention since the onset of the coronavirus disease 2019 (COVID-19) pandemic. However, clinical trials designed to study the efficacy of CPT based on antibody concentrations were inconclusive. Lymphatic transport is at the interplay between the immune response and the resolution of inflammation from peripheral tissues, including the artery wall. As vascular complications are a key pathogenic mechanism in COVID-19, leading to inflammation and multiple organ failure, we believe that sustaining lymphatic vessel function should be considered to define optimal CPT. We herein sought to determine what specific COVID-19 convalescent plasma (CCP) characteristics should be considered to limit inflammation-driven lymphatic endothelial cells (LEC) dysfunction. CCP donated 16 to 100 days after the last day of symptoms was characterized and incubated on inflammation-elicited adult human dermal LEC (aHDLEC). Plasma analysis revealed that late donation correlates with higher concentration of circulating pro-inflammatory cytokines. Conversely, extracellular vesicles (EVs) derived from LEC are more abundant in early donated plasma (r = −0.413, p = 0.004). Thus, secretion of LEC-EVs by an impaired endothelium could be an alarm signal that instigate the self-defense of peripheral lymphatic vessels against an excessive inflammation. Indeed, in vitro experiments suggest that CCP obtained rapidly following the onset of symptoms does not damage the aHDLEC junctions as much as late-donated plasma. We identified a particular signature of CCP that would counteract the effects of an excessive inflammation on the lymphatic endothelium. Accordingly, an easy and efficient selection of convalescent plasma based on time of donation would be essential to promote the preservation of the lymphatic and immune system of infected patients

Peripheral adaptive immunity of the triple transgenic mouse model of Alzheimer’s disease

Abstract Background Immunologic abnormalities have been described in peripheral blood and central nervous system of patients suffering from Alzheimer’s disease (AD), yet their role in the pathogenesis still remains poorly defined. Aim and methods We used the triple transgenic mouse model (3xTg-AD) to reproduce Aβ (amyloid plaques) and tau (neurofibrillary tangles) neuropathologies. We analyzed important features of the adaptive immune system in serum, primary (bone marrow) as well as secondary (spleen) lymphoid organs of 12-month-old 3xTg-AD mice using flow cytometry and ELISPOT. We further investigated serum cytokines of 9- and 13-month-old 3xTg-AD mice using multiplex ELISA. Results were compared to age-matched non-transgenic controls (NTg). Results In the bone marrow of 12-month-old 3xTg-AD mice, we detected decreased proportions of short-term reconstituting hematopoietic stem cells (0.58-fold, P = 0.0116), while lymphocyte, granulocyte, and monocyte populations remained unchanged. Our results also point to increased activation of both B and T lymphocytes. Indeed, we report elevated levels of plasma cells in bone marrow (1.3-fold, P = 0.0405) along with a 5.4-fold rise in serum IgG concentration (P < 0.0001) in 3xTg-AD animals. Furthermore, higher levels of interleukin (IL)-2 were detected in serum of 9- and 13-month-old 3xTg-AD mice (P = 0.0018). Along with increased concentrations of IL-17 (P = 0.0115) and granulocyte-macrophage colony-stimulating factor (P = 0.0085), these data support helper T lymphocyte activation with Th17 polarization. Conclusion Collectively, these results suggest that the 3xTg-AD model mimics modifications of the adaptive immunity changes previously observed in human AD patients and underscore the activation of both valuable and harmful pathways of immunity in AD

Evolution of Anti-RBD IgG Avidity following SARS-CoV-2 Infection

SARS-CoV-2 infection rapidly elicits anti-Spike antibodies whose quantity in plasma gradually declines upon resolution of symptoms. This decline is part of the evolution of an immune response leading to B cell differentiation into short-lived antibody-secreting cells or resting memory B cells. At the same time, the ongoing class switch and antibody maturation processes occurring in germinal centers lead to the selection of B cell clones secreting antibodies with higher affinity for their cognate antigen, thereby improving their functional activity. To determine whether the decline in SARS-CoV-2 antibodies is paralleled with an increase in avidity of the anti-viral antibodies produced, we developed a simple assay to measure the avidity of anti-receptor binding domain (RBD) IgG elicited by SARS-CoV-2 infection. We longitudinally followed a cohort of 29 convalescent donors with blood samples collected between 6- and 32-weeks post-symptoms onset. We observed that, while the level of antibodies declines over time, the anti-RBD avidity progressively increases and correlates with the B cell class switch. Additionally, we observed that anti-RBD avidity increased similarly after SARS-CoV-2 mRNA vaccination and after SARS-CoV-2 infection. Our results suggest that anti-RBD IgG avidity determination could be a surrogate assay for antibody affinity maturation and, thus, suitable for studying humoral responses elicited by natural infection and/or vaccination

A Recent SARS-CoV-2 Infection Enhances Antibody-Dependent Cellular Cytotoxicity against Several Omicron Subvariants following a Fourth mRNA Vaccine Dose

Since the beginning of the SARS-CoV-2 pandemic, several variants of concern (VOCs), such as the Alpha, Beta, Gamma, Delta and Omicron variants, have arisen and spread worldwide. Today, the predominant circulating subvariants are sublineages of the Omicron variant, which have more than 30 mutations in their Spike glycoprotein compared to the ancestral strain. The Omicron subvariants were significantly less recognized and neutralized by antibodies from vaccinated individuals. This resulted in a surge in the number of infections, and booster shots were recommended to improve responses against these variants. While most studies mainly measured the neutralizing activity against variants, we and others previously reported that Fc-effector functions, including antibody-dependent cellular cytotoxicity (ADCC), play an important role in humoral responses against SARS-CoV-2. In this study, we analyzed Spike recognition and ADCC activity against several Omicron subvariants by generating cell lines expressing different Omicron subvariant Spikes. We tested these responses in a cohort of donors, who were recently infected or not, before and after a fourth dose of mRNA vaccine. We showed that ADCC activity is less affected than neutralization by the antigenic shift of the tested Omicron subvariant Spikes. Moreover, we found that individuals with a history of recent infection have higher antibody binding and ADCC activity against all Omicron subvariants than people who were not recently infected. With an increase in the number of reinfections, this study helps better understand Fc-effector responses in the context of hybrid immunity