Innate Immune Cell Function Research Articles

Stretching the Function of Innate Immune Cells.

The importance of innate immune cells to sense and respond to their physical environment is becoming increasingly recognized. Innate immune cells (e.g. macrophages and neutrophils) are able to receive mechanical signals through several mechanisms. In this review, we discuss the role of mechanosensitive ion channels, such as Piezo1 and transient receptor potential vanilloid 4 (TRPV4), and cell adhesion molecules, such as integrins, selectins, and cadherins in biology and human disease. Furthermore, we explain that these mechanical stimuli activate intracellular signaling pathways, such as MAPK (p38, JNK), YAP/TAZ, EDN1, NF-kB, and HIF-1α, to induce protein conformation changes and modulate gene expression to drive cellular function. Understanding the mechanisms by which immune cells interpret mechanosensitive information presents potential targets to treat human disease. Important areas of future study in this area include autoimmune, allergic, infectious, and malignant conditions.

Reprogramming NK cells and macrophages via combined antibody and cytokine therapy primes tumors for elimination by checkpoint blockade.

SUMMARYTreatments aiming to augment immune checkpoint blockade (ICB) in cancer often focus on T cell immunity, but innate immune cells may have important roles to play. Here, we demonstrate a single-dose combination treatment (termed AIP) using a pan-tumor-targeting antibody surrogate, half-life-extended interleukin-2 (IL-2), and anti-programmed cell death 1 (PD-1), which primes tumors to respond to subsequent ICB and promotes rejection of large established tumors in mice. Natural killer (NK) cells and macrophages activated by AIP treatment underwent transcriptional reprogramming; rapidly killed cancer cells; governed the recruitment of cross-presenting dendritic cells (DCs) and other leukocytes; and induced normalization of the tumor vasculature, facilitating further immune infiltration. Thus, innate cell-activating therapies can initiate critical steps leading to a self-sustaining cycle of T cell priming driven by ICB.

Interferon-γ-Induced Myeloid-Derived Suppressor Cells Aggravate Kidney Ischemia-Reperfusion Injury by Regulating Innate Immune Cells

Objective: Myeloid-derived suppressor cells (MDSCs) are heterogeneous cells which can suppress T-cell functionality. Herein, we evaluated the functional importance of MDSCs in the context of kidney ischemia-reperfusion injury (IRI) and explored their ability to regulate innate and adaptive immune cell function in this context. Methods: The differentiation of MDSCs was induced in vitro by treating cells with GM-CSF and interferon (IFN)-γ. In a murine model of renal IRI, serum creatinine and blood urea nitrogen values were measured to monitor kidney function, while histopathological and immunohistochemical approaches were used to assess kidney injury severity. In addition, flow cytometry was employed to assess the phenotypes and apoptosis of kidney cells in these mice. Results: MDSCs induced by treatment with GM-CSF + IFN-γ could suppress T-cell functionality in vitro. The adoptive transfer of these MDSCs into an IRI mouse model system enhanced kidney damage and impaired renal function following the recruitment of these cells to renal tissues in these mice. Following such adoptive transfer, the relative frequency of MDSCs with a CD11b⁺Ly6G⁻Ly6C^high monocytic-MDSC phenotype decreased, whereas cells with a CD11b⁺Ly6G⁺Ly6C^low polymorphonuclear-MDSC phenotype become more prevalent within kidney tissues following IRI. Adoptive transfer also coincided with increased frequencies of macrophages and dendritic cells (DCs) in the kidney tissues. This suggested that M-MDSCs contributed to early-stage renal IRI damage by differentiating into these deleterious cell types. However, MDSC-induced suppression of CD4⁺ and CD8⁺ T-cell infiltration was not sufficient to prevent the deterioration of renal function in these mice. Conclusions: Herein, we successfully developed a protocol wherein MDSCs were differentiated in vitro through combination GM-CSF/IFN-γ treatment. When these MDSCs were subsequently adoptively transferred into a murine model of renal IRI, they aggravated kidney damage, likely owing to the differentiation of M-MDSCs into deleterious macrophages and DCs.

A Novel Regulatory Player in the Innate Immune System: Long Non-Coding RNAs.

Long non-coding RNAs (lncRNAs) represent crucial transcriptional and post-transcriptional gene regulators during antimicrobial responses in the host innate immune system. Studies have shown that lncRNAs are expressed in a highly tissue- and cell-specific- manner and are involved in the differentiation and function of innate immune cells, as well as inflammatory and antiviral processes, through versatile molecular mechanisms. These lncRNAs function via the interactions with DNA, RNA, or protein in either cis or trans pattern, relying on their specific sequences or their transcriptions and processing. The dysregulation of lncRNA function is associated with various human non-infectious diseases, such as inflammatory bowel disease, cardiovascular diseases, and diabetes mellitus. Here, we provide an overview of the regulation and mechanisms of lncRNA function in the development and differentiation of innate immune cells, and during the activation or repression of innate immune responses. These elucidations might be beneficial for the development of therapeutic strategies targeting inflammatory and innate immune-mediated diseases.

Critical Role of Zinc Transporter (ZIP8) in Myeloid Innate Immune Cell Function and the Host Response against Bacterial Pneumonia.

Zinc (Zn) is required for proper immune function and host defense. Zn homeostasis is tightly regulated by Zn transporters that coordinate biological processes through Zn mobilization. Zn deficiency is associated with increased susceptibility to bacterial infections, including Streptococcus pneumoniae, the most commonly identified cause of community-acquired pneumonia. Myeloid cells, including macrophages and dendritic cells (DCs), are at the front line of host defense against invading bacterial pathogens in the lung and play a critical role early on in shaping the immune response. Expression of the Zn transporter ZIP8 is rapidly induced following bacterial infection and regulates myeloid cell function in a Zn-dependent manner. To what extent ZIP8 is instrumental in myeloid cell function requires further study. Using a novel, myeloid-specific, Zip8 knockout model, we identified vital roles of ZIP8 in macrophage and DC function upon pneumococcal infection. Administration of S. pneumoniae into the lung resulted in increased inflammation, morbidity, and mortality in Zip8 knockout mice compared with wild-type counterparts. This was associated with increased numbers of myeloid cells, cytokine production, and cell death. In vitro analysis of macrophage and DC function revealed deficits in phagocytosis and increased cytokine production upon bacterial stimulation that was, in part, due to increased NF-κB signaling. Strikingly, alteration of myeloid cell function resulted in an imbalance of Th17/Th2 responses, which is potentially detrimental to host defense. These results (for the first time, to our knowledge) reveal a vital ZIP8- and Zn-mediated axis that alters the lung myeloid cell landscape and the host response against pneumococcus.

Comparative Expression Analysis of Innate Immune Markers and Phagocytic Activity in Peripheral Blood of Dogs with Mammary Tumors.

Simple SummaryThe presented study aimed to find out the differences between peripheral blood immune cell markers from healthy bitches and bitches with mammary tumors. Due to the fact that the role of canine innate immune cells in cancer remains poorly understood, the markers of innate cells were chosen for this research. Blood samples from female dogs with mammary tumors of epithelial and mesenchymal origin were investigated by flow cytometry. CD5 and CD11b markers of innate immune cells, phagocytic activity, and cellular killing were assessed. The number of CD11b lymphocytes was increased in tumors with epithelial origin. No significant differences were found between the percentages of phagocytic cells. However, the phagocytes of canine patients with tumors of epithelial origin showed increased phagocytosis compared to the control group. In oxidative burst test, a statistically significant difference between the number of reactive oxygen species (ROS) produced was demonstrated only between the group of bitches with epithelial tumors and the control group. These results may suggest that there are subpopulations of innate immune cells that may be involved in anti-tumor immune mechanisms and have a potential to be supportive diagnostic markers in canine mammary tumors.Canine innate immune system role in cancer prevention and progression remains poorly understood. It has been revealed that innate immune cells could play a dual role in cancer immunology promoting or inhibiting tumor development and growth. Current immunotherapies target mainly the adaptive anti-tumor response and that may be a reason why they remain ineffective in a majority of patients. It is important to acquire detailed knowledge about innate immune mechanisms to broaden the diagnostic and therapeutic options and employ innate immune cells in anti-cancer therapies. In the present study, 21 female dogs of different breeds and types of spontaneous mammary tumors were investigated. The study aimed to find simple and cheap markers that can be used for preliminary diagnosis, prior to the surgical resection of the tumor. The differences in innate immune cell quantity and function were investigated between female dogs with malignant mammary tumors of epithelial and mesenchymal origin. Flow cytometry was used to evaluate the percentages of CD5+ lymphocytes including CD5low lymphocytes, CD11b integrin expression on leukocytes, phagocytosis, and oxidative burst. The number of CD11b lymphocytes was increased in tumors with epithelial origin compared to the control group. No significant differences were found between the percentages of phagocytic cells neither for granulocytes nor for monocytes. However, the phagocytes of canine patients with tumors of epithelial origin showed increased phagocytosis compared to the control group. The percentages of granulocytes that produced reactive oxygen species (ROS) in response to E.coli and PMA were not altered in patients with malignant tumors compared to control. A statistically significant difference between the number of ROS produced by the single granulocyte was demonstrated only between the group of bitches with epithelial tumors and the control group in case of E. coli stimulation. The obtained results suggest that some innate immune cells may be involved in anti-tumor immune mechanisms and have the potential to be supportive diagnostic markers in canine mammary tumors.

Long-term effects of a short-term high-fat challenge on innate immune cell function in humans

Background and Aims: Triglyceride-rich lipoproteins (TRLs) are an independent risk factor for atherosclerotic cardiovascular disease (CVD). Monocyte-derived macrophages are regulators of the atherosclerotic process. We recently showed that monocytes can adopt a long-term pro-inflammatory phenotype upon brief stimulation with atherogenic stimuli, such as oxidized LDL. This is termed trained immunity. We hypothesized that a single high-fat challenge induces trained immunity, which could contribute to the atherogenic effects of transient postprandial TRL elevations.

Gut Microbiome and Metabolites in Systemic Lupus Erythematosus: Link, Mechanisms and Intervention.

Systemic lupus erythematosus (SLE), often considered the prototype of autoimmune diseases, is characterized by over-activation of the autoimmune system with abnormal functions of innate and adaptive immune cells and the production of a large number of autoantibodies against nuclear components. Given the highly complex and heterogeneous nature of SLE, the pathogenesis of this disease remains incompletely understood and is presumed to involve both genetic and environmental factors. Currently, disturbance of the gut microbiota has emerged as a novel player involved in the pathogenesis of SLE. With in-depth research, the understanding of the intestinal bacteria-host interaction in SLE is much more comprehensive. Recent years have also seen an increase in metabolomics studies in SLE with the attempt to identify potential biomarkers for diagnosis or disease activity monitoring. An intricate relationship between gut microbiome changes and metabolic alterations could help explain the mechanisms by which gut bacteria play roles in the pathogenesis of SLE. Here, we review the role of microbiota dysbiosis in the aetiology of SLE and how intestinal microbiota interact with the host metabolism axis. A proposed treatment strategy for SLE based on gut microbiome (GM) regulation is also discussed in this review. Increasing our understanding of gut microbiota and their function in lupus will provide us with novel opportunities to develop effective and precise diagnostic strategies and to explore potential microbiota-based treatments for patients with lupus.

Induction of T Cell Senescence by Cytokine Induced Bystander Activation.

As people around the world continue to live longer, maintaining a good quality of life is of increasing importance. The COVID-19 pandemic revealed that the elderly are disproportionally vulnerable to infectious diseases and Immunosenescence plays a critical role in that. An ageing immune system influences the conventional activity of T cells which are at the forefront of eliminating harmful foreign antigens. With ageing, unconventional end-stage T cells, that exhibit a senescent phenotype, amass. These senescent T cells deviate from T cell receptor (TCR) signaling toward natural killer (NK) activity. The transition toward innate immune cell function from these adaptor T cells impacts antigen specificity, contributing to increased susceptibility of infection in the elderly. The mechanism by which senescent T cells arise remains largely unclear however in this review we investigate the part that bystander activation plays in driving the change in function of T cells with age. Cytokine-induced bystander activation may offer a plausible explanation for the induction of NK-like activity and senescence in T cells. Further understanding of these specific NK-like senescent T cells allows us to identify the benefits and detriments of these cells in health and disease which can be utilized or regulated, respectively. This review discusses the dynamic of senescent T cells in adopting NK-like T cells and the implications that has in an infectious disease context, predominately in the elderly.

Staphylococcus aureus secreted lipases do not inhibit innate immune killing mechanisms.

Background: Staphylococcus aureus causes an array of diseases in both humans and livestock. Pathogenesis is mediated by a plethora of proteins secreted by S. aureus, many of which remain incompletely characterised. For example, S. aureus abundantly secretes two isoforms of the enzyme lipase into the extracellular milieu, where they scavenge upon polymeric triglycerides. It has previously been suggested that lipases may interfere with the function of innate immune cells, such as macrophages and neutrophils, but the impact of lipases on phagocytic killing mechanisms remains unknown. Methods: We employed the epidemic S. aureus clone USA300 strain LAC and its lipase deficient isogenic mutant, along with recombinant lipase proteins, in in vitro experimental infection assays. To determine if lipases can inhibit innate immune killing mechanisms, the bactericidal activity of whole blood, human neutrophils, and macrophages was analysed. In addition, gentamycin protection assays were carried out to examine the influence of lipases on S. aureus innate immune cell escape. Results: There were no differences in the survival of S. aureus USA300 LAC wild type and its lipase-deficient isogenic mutant after incubation with human whole blood or neutrophils. Furthermore, there was no detectable lipase-dependent effect on phagocytosis, intracellular survival, or escape from both human primary and immortalised cell line macrophages, even upon supplementation with exogenous recombinant lipases. Conclusions: S. aureus lipases do not inhibit bacterial killing mechanisms of human macrophages, neutrophils, or whole blood. These findings broaden our understanding of the interaction of S. aureus with the innate immune system.

Discrete Modes of Migration Define Human NK Cell Development from Hematopoietic Stem Cells

Human innate lymphoid cells play a critical role in the control of infection and the shaping of the immune response. Furthermore, natural killer (NK) cells are the first reconstituting lymphocyte population after hematopoietic stem cell transplant and play a key role in shaping engraftment and moderating graft vs. leukemic effects. Relative to their adaptive immune counterparts, the molecular interactions that drive innate immune cell differentiation development are poorly understood. Human NK cells arise from bone marrow CD34+ hematopoietic stem cells (HSC) but undergo maturation in distal microenvironments, the best characterized of which is secondary lymphoid tissue. Human NK cells can also be derived in vitro from CD34+ HSC through co-culture with developmentally supportive stromal cells. Despite the requirement for direct stromal cell contact in NK cell maturation, the nature of these contacts is not known. We have previously shown that freshly isolated human NK cell developmental intermediates from in vitro culture, secondary lymphoid tissue or peripheral blood undergo spontaneous migration on the EL08.1D2 stromal cell line. We have further defined the NK cell ‘developmental synapse’, a site of productive and directional signaling in developmental intermediates arrested on stromal cells. Despite these interesting insights, the regulation of, and requirement for, NK cell migration during differentiation has not been defined.To determine the modes of migration associated with human NK cell differentiation, we performed highly resolved continuous live cell imaging of NK cells developing in vitro from CD34+ HSC over 28 days of culture. These analyses were performed in parallel with flow cytometry to monitor the progression of developmental intermediates towards a functionally mature NK cell phenotype. We found that while CD34+ HSC had constrained motility, progressive NK cell differentiation was associated with more directed migratory phenotype. NK cell maturation was associated with increased track length and velocity, and decreased frequency of time of cells spent in arrest on stromal cells. We further defined the acquisition of complex, Levy-walk behavior as has previously been described for mature T cells imaged within tissue. The consistency of these behaviors between in vitro derived cells and fresh ex vivo NK cells isolated from healthy human donors confirms that in vitro differentiation effectively recapitulates migratory phenotypes in addition to functional and cell surface phenotypes associated with NK cell maturation.Together, these data define distinct modes of migration that are acquired by human NK cells. We propose that this reflects a previously unappreciated requirement for cell migration that enables the functional maturation of human NK cells. Better defining the bidirectional signaling between developing NK cells and their microenvironment will enable a complete understanding of the signals that help shape the acquisition of key innate immune cell functions. This understanding is critical for better predicting and therapeutically enhancing lymphocyte reconstitution after transplant. DisclosuresNo relevant conflicts of interest to declare.

Extracellular Vesicles in Innate Immune Cell Programming.

Extracellular vesicles (EV) are a heterogeneous group of bilipid-enclosed envelopes that carry proteins, metabolites, RNA, DNA and lipids from their parent cell of origin. They mediate cellular communication to other cells in local tissue microenvironments and across organ systems. EV size, number and their biologically active cargo are often altered in response to pathological processes, including infection, cancer, cardiovascular diseases and in response to metabolic perturbations such as obesity and diabetes, which also have a strong inflammatory component. Here, we discuss the broad repertoire of EV produced by neutrophils, monocytes, macrophages, their precursor hematopoietic stem cells and discuss their effects on the innate immune system. We seek to understand the immunomodulatory properties of EV in cellular programming, which impacts innate immune cell differentiation and function. We further explore the possibilities of using EV as immune targeting vectors, for the modulation of the innate immune response, e.g., for tissue preservation during sterile injury such as myocardial infarction or to promote tissue resolution of inflammation and potentially tissue regeneration and repair.

Differential Modulation of 25-hydroxycholecalciferol on Innate Immunity of Broiler Breeder Hens.

Simple SummaryNo predominant changes between R- vs. Ad-feed intake on leukocyte defense against pathogens were observed in broiler breeder hens despite some differences in inflammatory and respiratory burst responses. Overall, supplemental 25-OH-D3 had more pronounced effects on the innate immunity of Ad-hens. In vitro studies confirmed the differential effects of 25-OH-D3 to rescue immune functions altered by glucose and/or palmitic acid exposure.Past immunological studies in broilers focused on juveniles within the rapid pre-slaughter growth period and may not reflect adult immune responses, particularly in breeders managed with chronic feed restriction (R). The study aimed to assess innate immune cell functions in respect to R vs. ad libitum (Ad) feed intake in breeder hens with and without dietary 25-hydroxycholecalciferol (25-OH-D3) supplementation. Ad-feed intake consistently suppressed IL-1β secretion, respiratory burst, and cell livability in peripheral heterophils and/or monocytes along the feeding trial from the age of 51 to 68 weeks. Supplemental 25-OH-D3 repressed IL-1β secretion and respiratory burst of both cells mostly in R-hens, but promoted monocyte phagocytosis, chemotaxis, and bacterial killing activity in Ad-hens in accompany with relieved hyperglycemia, hyperlipidemia, and systemic inflammation. Overnight cultures with leukocytes from R-hens confirmed the differential effects of 25-OH-D3 to rescue immune functions altered by glucose and/or palmitic acid exposure. Studies with specific inhibitors further manifested the operative mechanisms via glucolipotoxicity in a cell type- and function-dependent manner. The results concluded no predominant changes between R- vs. Ad-feed intake on leukocyte defense against pathogens despite some differential differences, but supplemental 25-OH-D3 exerts more pronounced effects in Ad-hens.

Innate immune cells in the tumor microenvironment.

The tumor immune microenvironment (TIME) is a complex ecosystem that contains adaptive and innate immune cells that have tumor-promoting and anti-tumor effects. There is still much to learn about the diversity, plasticity, and functions of innate immune cells in the TIME and their roles in determining the response to immunotherapies. Experts discuss recent advances in our understanding of their biology in cancer as well as outstanding questions and potential therapeutic avenues.

Perinatal development of innate immune topology.

At the transition from intrauterine to postnatal life, drastic alterations are mirrored by changes in cellular immunity. These changes are in part immune cell intrinsic, originate in the replacement of fetal cells, or result from global regulatory mechanisms and adaptation to changes in the tissue microenvironment. Overall, longer developmental trajectories are intersected by events related to mother-infant separation, birth cues, acquisition of microbiota and metabolic factors. Perinatal alterations particularly affect immune niches, where structures with discrete functions meet, the intestinal mucosa, epidermis and lung. Accordingly, the following questions will be addressed in this review:How does the preprogrammed development supported by endogenous cues, steer innate immune cell differentiation, adaptation to tissue structures, and immunity to infection?How does the transition at birth impact on tissue immune make-up including its topology?How do postnatal cues guide innate immune cell differentiation and function at immunological niches?

STING regulates metabolic reprogramming in macrophages via HIF-1α during Brucella infection

Macrophages metabolic reprogramming in response to microbial insults is a major determinant of pathogen growth or containment. Here, we reveal a distinct mechanism by which stimulator of interferon genes (STING), a cytosolic sensor that regulates innate immune responses, contributes to an inflammatory M1-like macrophage profile upon Brucella abortus infection. This metabolic reprogramming is induced by STING-dependent stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), a global regulator of cellular metabolism and innate immune cell functions. HIF-1α stabilization reduces oxidative phosphorylation and increases glycolysis during infection with B. abortus and, likewise, enhances nitric oxide production, inflammasome activation and IL-1β release in infected macrophages. Furthermore, the induction of this inflammatory profile participates in the control of bacterial replication since absence of HIF-1α renders mice more susceptible to B. abortus infection. Mechanistically, activation of STING by B. abortus infection drives the production of mitochondrial reactive oxygen species (mROS) that ultimately influences HIF-1α stabilization. Moreover, STING increases the intracellular succinate concentration in infected macrophages, and succinate pretreatment induces HIF-1α stabilization and IL-1β release independently of its cognate receptor GPR91. Collectively, these data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during B. abortus infection that is orchestrated by STING via HIF-1α pathway and highlight the metabolic reprogramming of macrophages as a potential treatment strategy for bacterial infections.

ST8Sia6 Overexpression Accelerates Tumorigenesis in a Siglec-E Dependent Manner Through Reshaping the Tumor Immune Microenvironment

Abstract Checkpoint blockade has improved patient outcome through reinvigorating T cells against cancer. Despite this success, many patients don’t respond, leaving them with few options. Tumors utilize many immunosuppressive mechanisms, including altering the function of innate immune cells. Cancer cells can promote differentiation of macrophages into tolerogenic “M2-like” macrophages, which support tumor growth. Macrophage differentiation by cancer cells is influenced by many receptors, including Siglec-E. Siglec-E binds to α2,8-linked disialic acids, generated by the enzyme ST8Sia6, on O-linked glycoproteins, and functions to inhibit activation of innate immune cells. In some tumor types, higher expression of ST8Sia6 correlates with poorer survival. Therefore, ST8Sia6 overexpressing tumors may engage Siglec-E, leading to immune suppression and accelerating tumor growth. Mice injected with ST8Sia6 overexpressing MC38 and B16-F10 tumors had increased tumor burden, reduced survival and increased M2 macrophage polarization, which suppresses the immune response. This acceleration of tumor growth was abrogated when injected into Siglec-E knockout mice. Thus, the primary function of ST8Sia6 in tumors is an extrinsic alteration of the immune response, rather than an intrinsic effect on cell growth. Similarly, in a spontaneous colon cancer model, ST8Sia6 overexpression in a murine colon cancer model accelerated the development of tumors, decreasing survival to 2.5 months instead of 6 months. The overexpression of ST8Sia6 leads to increased Arg-1 expression by colonic tumor macrophages. Therefore, ST8Sia6 expression in tumors inhibits the immune response to promote tumor growth in a Siglec-E dependent manner.

Salt Transiently Inhibits Mitochondrial Energetics in Mononuclear Phagocytes.

Dietary high salt (HS) is a leading risk factor for mortality and morbidity. Serum sodium transiently increases postprandially but can also accumulate at sites of inflammation affecting differentiation and function of innate and adaptive immune cells. Here, we focus on how changes in extracellular sodium, mimicking alterations in the circulation and tissues, affect the early metabolic, transcriptional, and functional adaption of human and murine mononuclear phagocytes. Using Seahorse technology, pulsed stable isotope-resolved metabolomics, and enzyme activity assays, we characterize the central carbon metabolism and mitochondrial function of human and murine mononuclear phagocytes under HS in vitro. HS as well as pharmacological uncoupling of the electron transport chain under normal salt is used to analyze mitochondrial function on immune cell activation and function (as determined by Escherichiacoli killing and CD4+ T cell migration capacity). In 2 independent clinical studies, we analyze the effect of a HS diet during 2 weeks (URL: http://www.clinicaltrials.gov. Unique identifier: NCT02509962) and short-term salt challenge by a single meal (URL: http://www.clinicaltrials.gov. Unique identifier: NCT04175249) on mitochondrial function of human monocytes in vivo. Extracellular sodium was taken up into the intracellular compartment, followed by the inhibition of mitochondrial respiration in murine and human macrophages. Mechanistically, HS reduces mitochondrial membrane potential, electron transport chain complex II activity, oxygen consumption, and ATP production independently of the polarization status of macrophages. Subsequently, cell activation is altered with improved bactericidal function in HS-treated M1-like macrophages and diminished CD4+ T cell migration in HS-treated M2-like macrophages. Pharmacological uncoupling of the electron transport chain under normal salt phenocopies HS-induced transcriptional changes and bactericidal function of human and murine mononuclear phagocytes. Clinically, also in vivo, rise in plasma sodium concentration within the physiological range reversibly reduces mitochondrial function in human monocytes. In both a 14-day and single meal HS challenge, healthy volunteers displayed a plasma sodium increase of [Formula: see text] and [Formula: see text] respectively, that correlated with decreased monocytic mitochondrial oxygen consumption. Our data identify the disturbance of mitochondrial respiration as the initial step by which HS mechanistically influences immune cell function. Although these functional changes might help to resolve bacterial infections, a shift toward proinflammation could accelerate inflammatory cardiovascular disease.

Reduced phagocytosis, ROS production and enhanced apoptosis of leukocytes upon alcohol drinking in healthy volunteers

BackgroundAlcohol drinking is associated with a serious risk of developing health problems as well as with a large number of traumatic injuries. Although chronic alcohol misuse is known to contribute to severe inflammatory complications, the effects of an acute alcohol misuse are still unclear. Here, the impact of acute alcohol drinking on leukocyte counts and their cellular functions were studied.MethodsTwenty-two healthy volunteers (12 female, 10 male) received a predefined amount of a whiskey-cola mixed drink (40% v/v), at intervals of 20 min, over 4 h to achieve a blood alcohol concentration of 1‰. Blood samples were taken before drinking T0, 2 h (T2), 4 h (T4), 6 h (T6), 24 h (T24) and 48 h (T48) after starting drinking alcohol. Leukocytes, monocytes and granulocyte counts and their functions regarding the production of reactive oxidative species (ROS), phagocytosis and apoptosis were analyzed by flow cytometry.ResultsTotal leukocyte counts significantly increased at T2 and T4, while granulocyte and monocyte counts decreased at T4 and T6 vs. T0. Monocytes increased significantly at T24 and T48 vs. T0. While the total number of ROS-producing leukocytes and notably granulocytes significantly increased, in parallel, the intracellular ROS intensity decreased at T2 and T6. The numbers of ROS-positive monocytes have shown a delayed modulation of ROS, with a significant reduction in the total number of ROS-producing cells at T48 and a significantly reduced intracellular ROS-intensity at T24. Phagocyting capacity of leukocytes significantly decreased at T4 and T6. In general leukocytes, and notably granulocytes demonstrated significantly increased early (T2), while monocyte exerted significantly increased late apoptosis (T24 and T48).ConclusionsAlcohol drinking immediately impacts leukocyte functions, while the impact on monocytes occurs at even later time points. Thus, even in young healthy subjects, alcohol drinking induces immunological changes that are associated with diminished functions of innate immune cells that persist for days.

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia.

Simple SummaryStudies conducted in a recent decade revealed that acute lymphoblastic leukemia cells exploit various mechanisms to avoid immune recognition and destruction by the immune system. As a consequence, leukemia cells become more resistant to treatment, which results in poor patient outcomes. In this review, we describe the interactions between acute lymphoblastic leukemia (ALL) cells and selected populations of immune cells within the bone marrow microenvironment that contribute to leukemia development, promotion, and relapse. We also discuss how various elements of the bone marrow niche affect ALL chemo- and immunotherapy and present recently discovered treatment strategies that restore or stimulate the immune response to ALL.Acute lymphoblastic leukemia (ALL) results from a clonal expansion of abnormal lymphoid progenitors of B cell (BCP-ALL) or T cell (T-ALL) origin that invade bone marrow, peripheral blood, and extramedullary sites. Leukemic cells, apart from their oncogene-driven ability to proliferate and avoid differentiation, also change the phenotype and function of innate and adaptive immune cells, leading to escape from the immune surveillance. In this review, we provide an overview of the genetic heterogeneity and treatment of BCP- and T-ALL. We outline the interactions of leukemic cells in the bone marrow microenvironment, mainly with mesenchymal stem cells and immune cells. We describe the mechanisms by which ALL cells escape from immune recognition and elimination by the immune system. We focus on the alterations in ALL cells, such as overexpression of ligands for various inhibitory receptors, including anti-phagocytic receptors on macrophages, NK cell inhibitory receptors, as well as T cell immune checkpoints. In addition, we describe how developing leukemia shapes the bone marrow microenvironment and alters the function of immune cells. Finally, we emphasize that an immunosuppressive microenvironment can reduce the efficacy of chemo- and immunotherapy and provide examples of preclinical studies showing strategies for improving ALL treatment by targeting these immunosuppressive interactions.