IRF5 Is a Key Regulator of Macrophage Response to Lipopolysaccharide in Newborns.

Infections are a leading cause of mortality and morbidity in newborns. The high susceptibility of newborns to infection has been associated with a limited capacity to mount protective immune responses. Monocytes and macrophages are involved in the initiation, amplification, and termination of immune responses. Depending on cues received from their environment, monocytes differentiate into M1 or M2 macrophages with proinflammatory or anti-inflammatory and tissue repair properties, respectively. The purpose of this study was to characterize differences in monocyte to macrophage differentiation and polarization between newborns and adults. Monocytes from umbilical cord blood of healthy term newborns and from peripheral blood of adult healthy subjects were exposed to GM-CSF or M-CSF to induce M1 or M2 macrophages. Newborn monocytes differentiated into M1 and M2 macrophages with similar morphology and expression of differentiation/polarization markers as adult monocytes, with the exception of CD163 that was expressed at sevenfold higher levels in newborn compared to adult M1 macrophages. Upon TLR4 stimulation, newborn M1 macrophages produced threefold to sixfold lower levels of TNF than adult macrophages, while production of IL-1-β, IL-6, IL-8, IL-10, and IL-23 was at similar levels as in adults. Nuclear levels of IRF5, a transcription factor involved in M1 polarization, were markedly reduced in newborns, whereas the NF-κB and MAP kinase pathways were not altered. In line with a functional role for IRF5, adenoviral-mediated IRF5 overexpression in newborn M1 macrophages restored lipopolysaccharide-induced TNF production. Altogether, these data highlight a distinct immune response of newborn macrophages and identify IRF5 as a key regulator of macrophage TNF response in newborns

Impact of the microbial derived short chain fatty acid propionate on host susceptibility to bacterial and fungal infections in vivo.

Short chain fatty acids (SCFAs) produced by intestinal microbes mediate anti-inflammatory effects, but whether they impact on antimicrobial host defenses remains largely unknown. This is of particular concern in light of the attractiveness of developing SCFA-mediated therapies and considering that SCFAs work as inhibitors of histone deacetylases which are known to interfere with host defenses. Here we show that propionate, one of the main SCFAs, dampens the response of innate immune cells to microbial stimulation, inhibiting cytokine and NO production by mouse or human monocytes/macrophages, splenocytes, whole blood and, less efficiently, dendritic cells. In proof of concept studies, propionate neither improved nor worsened morbidity and mortality parameters in models of endotoxemia and infections induced by gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae), gram-positive bacteria (Staphylococcus aureus, Streptococcus pneumoniae) and Candida albicans. Moreover, propionate did not impair the efficacy of passive immunization and natural immunization. Therefore, propionate has no significant impact on host susceptibility to infections and the establishment of protective anti-bacterial responses. These data support the safety of propionate-based therapies, either via direct supplementation or via the diet/microbiota, to treat non-infectious inflammation-related disorders, without increasing the risk of infection

Sirtuin 5 Deficiency Does Not Compromise Innate Immune Responses to Bacterial Infections.

Sirtuin 5 (SIRT5) is a member of the family of NAD <sup>+</sup> -dependent lysine/histone deacetylases. SIRT5 resides mainly in the mitochondria where it catalyzes deacetylation, demalonylation, desuccinylation, and deglutarylation of lysine to regulate metabolic and oxidative stress response pathways. Pharmacologic inhibitors of SIRT5 are under development for oncologic conditions, but nothing is known about the impact of SIRT5 on antimicrobial innate immune defenses. Using SIRT5 knockout mice, we show that SIRT5 deficiency does not affect immune cell development, cytokine production and proliferation by macrophages and splenocytes exposed to microbial and immunological stimuli. Moreover, preclinical models suggest that SIRT5 deficiency does not worsen endotoxemia, Klebsiella pneumoniae and Streptococcus pneumoniae pneumonia, Escherichia coli peritonitis, listeriosis, and staphylococcal infection. Altogether, these data support the safety profile in terms of susceptibility to infections of SIRT5 inhibitors under development

Emerging single-cell technologies in immunology.

During evolution, the immune system has diversified to protect the host from the extremely wide array of possible pathogens. Until recently, immune responses were dissected by use of global approaches and bulk tools, averaging responses across samples and potentially missing particular contributions of individual cells. This is a strongly limiting factor, considering that initial immune responses are likely to be triggered by a restricted number of cells at the vanguard of host defenses. The development of novel, single-cell technologies is a major innovation offering great promise for basic and translational immunology with the potential to overcome some of the limitations of traditional research tools, such as polychromatic flow cytometry or microscopy-based methods. At the transcriptional level, much progress has been made in the fields of microfluidics and single-cell RNA sequencing. At the protein level, mass cytometry already allows the analysis of twice as many parameters as flow cytometry. In this review, we explore the basis and outcome of immune-cell diversity, how genetically identical cells become functionally different, and the consequences for the exploration of host-immune defense responses. We will highlight the advantages, trade-offs, and potential pitfalls of emerging, single-cell-based technologies and how they provide unprecedented detail of immune responses

Does a strong <weak> dollar imply a weak <strong> DM in the EMS Empirical test and theoretical explanation

SIGLEBibliothek Weltwirtschaft Kiel C130,749 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

High-dimensional immune phenotyping of blood cells by mass cytometry in patients infected with hepatitis C virus.

Chronic hepatitis C virus (HCV) infection affects the immune system. Whether elimination of HCV with direct-acting antivirals (DAA) restores immunity is unclear. We used mass cytometry to get a broad and in-depth assessment of blood cell populations of patients with chronic HCV prior to and after DAA therapy. Before and 12 weeks after sustained virological response to DAA therapy (SVR12), 22 cell populations were analysed by mass cytometry in blood collected from 10 healthy controls and 20 HCV patients with (10) or without human immunodeficiency virus (HIV) (10) infection. HCV infection altered the frequency of 14/22 (64%) blood cell populations. At baseline, the frequencies (median [IQR]; control, HCV, HCV/HIV) of intermediate monocytes (1.2 [0.47-1.46], 1.76 [0.83-2.66], 0.78 [0.28-1.77]), non-classical monocytes (1.11 [0.49-1.26], 0.9 [0.18-0.99], 0.54 [0.28-1.77]), conventional dendritic cells type 2 (0.55 [0.35-0.59], 0.31 [0.16-0.38], 0.19 [0.11-0.36]) and CD56 <sup>dim</sup> natural killer cells (8.08 [5.34-9.79], 4.72 [2.59-6.05], 3.61 [2.98-5.07]) were reduced by 35% to 65%, particularly in HCV/HIV co-infected patients. In contrast, activated double-negative T cells (0.07 [0.06-0.10], 0.10 [0.09-0.19], 0.19 [0.12-0.25]), activated CD4 T cells (0.28 [0.21-0.36], 0.56 [0.33-0.77], 0.40 [0.22-0.53]) and activated CD8 T cells (0.23 [0.14-0.42], 0.74 [0.30-1.65], 0.80 [0.58-1.16]) were increased 1.4 to 3.5 times. Upon stimulation with Toll-like receptor ligands, the expression of cytokines was up-regulated in 7/9 (78%) and 17/19 (89%) of the conditions in HCV and HCV/HIV patients, respectively. Most alterations persisted at SVR12. Chronic HCV and HCV/HIV infections induces profound and durable perturbations of innate and adaptive immune homeostasis