Activation Of Mononuclear Phagocytes Research Articles

Effect of extracellular adenosine triphosphate hydrolysis by apyrase on bleomycin-induced circulating and alveolar mononuclear phagocyte activation and lung inflammation.

Effect of extracellular adenosine triphosphate hydrolysis by apyrase on bleomycin-induced circulating and alveolar mononuclear phagocyte activation and lung inflammation.

The Pathophysiology of Trypanosomiosis Associated Anaemia: A Multifactoral Phenomenon

The pathobiology of anaemia in trypanosomiosis remains one of the aspects that still lacks thorough understanding. Extra vascular haemolysis is often identified as a major contributor to anaemia, primarily due to the mononuclear phagocytic activity of the host. This sets off a series of reactions, ultimately resulting in a significant alterations in haemato-biochemical indices. The magnitude of these alterations becomes more pronounced during successive waves of fluctuating parasitemia. However, it's important to note that the basic cause of anaemia is intricate and typically multifaceted, mainly affecting the cellular integrity of red blood cells, terminating into hemolytic anemia and/or increased erythrophagocytosis. Injuries inflicted by the flagella and microtubules of the parasite onto the membranes of erythrocytes further facilitate erythrophagocytosis of damaged RBCs. Additionally, erythrocytes, reticulocytes, and platelets often bind to trypanosomes via. sialic acid receptors, causing injuries to the cells promoting their rupture. A number of factors attributing to haemolytic anaemia include trypanosome are discussed in the present review. This review elaborates on the details and interactions of all these contributing factors

Bromodomain Inhibitors Modulate FcγR-Mediated Mononuclear Phagocyte Activation and Chemotaxis.

IgG antibodies form immune complexes (IC) that propagate inflammation and tissue damage in autoimmune diseases such as systemic lupus erythematosus. IgG IC engage Fcγ receptors (FcγR) on mononuclear phagocytes (MNP), leading to widespread changes in gene expression that mediate antibody effector function. Bromodomain and extra-terminal domain (BET) proteins are involved in governing gene transcription. We investigated the capacity of BET protein inhibitors (iBET) to alter IgG FcγR-mediated MNP activation. We found that iBET dampened IgG IC-induced pro-inflammatory gene expression and decreased activating FcγR expression on MNPs, reducing their ability to respond to IgG IC. Despite FcγR downregulation, iBET-treated macrophages demonstrated increased phagocytosis of protein antigen, IgG IC, and apoptotic cells. iBET also altered cell morphology, generating more amoeboid MNPs with reduced adhesion. iBET treatment impaired chemotaxis towards a CCL19 gradient in IC-stimulated dendritic cells (DC) in vitro, and inhibited IC-induced DC migration to draining lymph nodes in vivo, in a DC-intrinsic manner. Altogether, our data show that iBET modulates FcγR-mediated MNP activation and migration, revealing the therapeutic potential of BET protein inhibition in antibody-mediated diseases.

Focused ultrasound effects on the glioblastoma immune microenvironment

Focused ultrasound (FUS) is an attractive method of treating neurological diseases, such as glioblastoma (GBM). An accumulating body of evidence has confirmed the efficacy and safety of using FUS with systematically circulating microbubbles, which operate as acoustic enhancers, to temporarily open the blood-brain barrier for drug delivery. However, there is very limited knowledge of how immune cell respond to mechanical stimuli such as FUS, particularly in the complex immune microenvironments of brain tumors. Here, we report FUS immunomodulation effects may also include the enhanced recruitment and activation of other mononuclear phagocytes in murine models of GBM in tests with or without monoclonal antibody-based passive immunotherapy. Flow cytometry, immunohistochemistry, and in vitro cell co-culture studies were performed for immunoprofiling and immune effector determination. In murine GBM models, our results demonstrated that FUS enhanced antigen presentation behaviors of tumor-associated macrophages without affecting the microglia. FUS also reprogrammed the macrophages locally towards the anti-cancer phenotype. Taken together, our results offer new evidence in FUS immunomodulation on the myeloid compartment of the brains in GBM mouse models.

Interleukin-2 in the Complex Treatment of Surgical Patients

Immunotherapy for surgical diseases remains one of the urgent scientific and clinical issues. Immunodeficiency is manifested in patients with purulent wounds, pancreatic necrosis, osteomyelitis, oncological diseases, echinococcosis, gastroduodenal ulcers and other pathology. Drugs inducing interleukin-2 synthesis have shown high efficacy for the correction of immunodeficiency status. Clinical effects of rIL-2 are due to its ability to activate clonal proliferation of T- and B-lymphocytes, to enhance the effector potential of cytotoxic T-lymphocytes (CTL cells) and natural killer cells (NK cells), functional activity of mononuclear phagocytes and antigen-presenting cells, synthesis of specific immunoglobulins of most isotypes by plasma cells and to reduce apoptosis of mononuclears. This cytokine is a key link determining the development of cellular and humoral immunity. Interleukin-2 provides antitumor, antiviral, antibacterial and antifungal protection, being able to stimulate the processes of tissue regeneration and repair. The high clinical activity of the drug was revealed in the treatment of endotoxicosis, immunological insufficiency, inflammatory diseases in patients with surgical, oncological, traumatological, combustiological, resuscitation profiles, involving abdominal organs, pelvis and retroperitoneal space. It is rational to use recombinant interleukin-2 in case of previous inefficient conventional treatment and the process chronization. The drug has a number of positive aspects: rapid effect; reduced terms of treatment, frequency of infectious complications and sepsis; reduced mortality rate. The negative side of its administration is its high cost. Thus, immunosuppressive conditions are manifested in multiple surgical diseases. High clinical efficacy of recombinant interleukin 2, absence of complications, adverse reactions and undesirable effects, and favourable tolerability of the drug allow recommending it for wider use in surgical practice.

Myeloid cell modulation by a GLP-1 receptor agonist regulates retinal angiogenesis in ischemic retinopathy.

Ischemic retinopathies including diabetic retinopathy are major causes of blindness. Although neurons and Müller glia are recognized as important regulators of reparative and pathologic angiogenesis, the role of mononuclear phagocytes (MPs) — particularly microglia, the resident retinal immune cells — is unclear. Here, we found MP activation in human diabetic retinopathy, especially in neovessels from human neovascular membranes in proliferative retinopathy, including TNF-α expression. There was similar activation in the mouse oxygen-induced retinopathy (OIR) model of ischemia-induced neovascularization. Glucagon-like peptide-1 receptor (GLP-1R) agonists are in clinical use for glycemic control in diabetes and are also known to modulate microglia. Herein, we investigated the effect of a long-acting GLP-1R agonist, NLY01. Following intravitreal administration, NLY01 selectively localized to MPs in retina with OIR. NLY01 modulated MPs but not retinal endothelial cell viability, apoptosis, and tube formation in vitro. In OIR, NLY01 treatment inhibited MP infiltration and activation, including MP expression of cytokines in vivo. NLY01 significantly suppressed global induction of retinal inflammatory cytokines, promoted reparative angiogenesis, and suppressed pathologic retinal neovascularization. Collectively, these findings indicate the important role of mononuclear phagocytes in regulation of retinal vascularization in ischemia and suggest modulation of MPs as a potentially new treatment strategy for ischemic retinopathies.

Defining the Innate Immune Responses for SARS-CoV-2-Human Macrophage Interactions.

Host innate immune response follows severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and it is the driver of the acute respiratory distress syndrome (ARDS) amongst other inflammatory end-organ morbidities. Such life-threatening coronavirus disease 2019 (COVID-19) is heralded by virus-induced activation of mononuclear phagocytes (MPs; monocytes, macrophages, and dendritic cells). MPs play substantial roles in aberrant immune secretory activities affecting profound systemic inflammation and end-organ malfunctions. All follow the presence of persistent viral components and virions without evidence of viral replication. To elucidate SARS-CoV-2-MP interactions we investigated transcriptomic and proteomic profiles of human monocyte-derived macrophages. While expression of the SARS-CoV-2 receptor, the angiotensin-converting enzyme 2, paralleled monocyte-macrophage differentiation, it failed to affect productive viral infection. In contrast, simple macrophage viral exposure led to robust pro-inflammatory cytokine and chemokine expression but attenuated type I interferon (IFN) activity. Both paralleled dysregulation of innate immune signaling pathways, specifically those linked to IFN. We conclude that the SARS-CoV-2-infected host mounts a robust innate immune response characterized by a pro-inflammatory storm heralding end-organ tissue damage.

Focused ultrasound immunomodulation on mononuclear phagocytes in the brain

Focused ultrasound (FUS)-mediated blood–brain barrier opening is an attractive method of treating neurological diseases, such as glioblastoma (GBM) and Alzheimer’s disease (AD). As an established drug delivery approach, FUS has also been associated with the stimulation of neuro-inflammation, including the morphological activation of resident microglia. Here we report FUS immunomodulation effects may also include the enhanced recruitment and activation of other mononuclear phagocytes in murine models of GBM (GL261) and AD (APP/PS1dE9) in tests with or without monoclonal antibody-based passive immunotherapy. Immunoprofiling via flow cytometry and immunofluorescent staining were performed in the harvested brains. In the GBM model, our results demonstrated that FUS enhanced antigen presentation behaviors of tumor-associated macrophages without affecting the microglia. FUS also reprogrammed the macrophages locally towards the anti-cancer phenotype. In the AD model, plaque-associated Ly6G+ phagocytes were only present in FUS-treated areas, while microglia activation was found in both antibody-treated groups. Taken together, our results offer new evidence in FUS immunomodulation on the myeloid compartment of the brains in GBM and AD-like mouse models.

The Immunopathobiology of SARS-CoV-2 Infection.

ABSTRACTInfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to coronavirus disease 2019 (COVID-19). Virus-specific immunity controls infection, transmission and disease severity. With respect to disease severity, a spectrum of clinical outcomes occur associated with age, genetics, comorbidities and immune responses in an infected person. Dysfunctions in innate and adaptive immunity commonly follow viral infection. These are heralded by altered innate mononuclear phagocyte differentiation, activation, intracellular killing and adaptive memory, effector, and regulatory T cell responses. All of such affect viral clearance and the progression of end-organ disease. Failures to produce effective controlled antiviral immunity leads to life-threatening end-organ disease that is typified by the acute respiratory distress syndrome. The most effective means to contain SARS-CoV-2 infection is by vaccination. While an arsenal of immunomodulators were developed for control of viral infection and subsequent COVID-19 disease, further research is required to enable therapeutic implementation.

Indicators of total homeostasis in cows in different periods of lactations

The immunomorphological parameters of cattle in different periods of lactation were studied. In the first 3 months of lactation, excluding 7 days of the colostrum period, 59.3 units of circulating immune complexes were found in the serum, in the middle of lactation (4–7 months) – 94.2 (p <0.05), at the end (8–10 months) – 94.1 units (p <0.05). The significant difference between the indicator in the first 3 months and in the subsequent periods of lactation is due to the fact that at the beginning of lactation the cows were not yet pregnant. In the colostrum period, a high rate of circulating immune complexes of 116.1 units (p <0.05) was determined as a consequence of a fetal prenatal immune attack on the cow's body, when the system of mononuclear phagocytes had not yet coped with the elimination of neutralization products. During the dry period, the number of circulating immune complexes was 87.6 units (p <0.05). The decrease in the indicator occurred due to an increase in the activity of mononuclear phagocytes and the absence of lactation effect on the body. The content of segmental, functionally mature leukocytes at the beginning of lactation was 39.4%, in the middle of lactation this indicator decreased to 24.8% (p<0.05), at the end it was 26.3% (p<0.05). A significant difference was found in the relative number of segmented neutrophils in the control group and in non-lactating cows in the dry period – 29.9% (p <0.05). During the colostrum period, the level of lymphocytes in the blood of animals was 62.0% (p <0.05) and it significantly differed from the control – 43.6%. In the middle and at the end of lactation, there was also a significant difference between the indicator and the control, up to 58.9–59.4% (p<0.05). A significant difference with the group of down-calving dry cows was established – 53.9% (p <0.05). In the first 1–3 months of lactation, cows are either not yet pregnant, or a close bond (placenta) between the mother and the fetus has not yet been formed, therefore a low activity of specific immunity at this time is caused by the absence of foreign fetal antigens in the blood of cows. The findings suggest that the birth process may be initiated by the immune system.

TREM-1+ Macrophages Define a Pathogenic Cell Subset in the Intestine of Crohn's Disease Patients.

Background and AimsUncontrolled activation of intestinal mononuclear phagocytes [MNPs] drives chronic inflammation in inflammatory bowel disease [IBD]. Triggering receptor expressed on myeloid cells 1 [TREM-1] has been implicated in the pathogenesis of IBD. However, the role of TREM-1+ cell subsets in driving IBD pathology and the link with clinical parameters are not understood. We investigated TREM-1 expression in human intestinal MNP subsets and examined blocking TREM-1 as a potential IBD therapy.Methods TREM-1 gene expression was analysed in intestinal mucosa, enriched epithelial and lamina propria [LP] layers, and purified cells from controls and IBD patients. TREM-1 protein on immune cells was assessed by flow cytometry and immunofluorescence microscopy. Blood monocyte activation was examined by large-scale gene expression using a TREM-1 agonist or LP conditioned media [LP-CM] from patients in the presence or absence of TREM-1 and tumour necrosis factor [TNF] antagonist antibodies.Results TREM-1 gene expression increases in intestinal mucosa from IBD patients and correlates with disease score. TREM-1+ cells, which are mainly immature macrophages and CD11b+ granulocytes, increase among LP cells from Crohn’s disease patients and their frequency correlates with inflammatory molecules in LP-CM. LP-CM from Crohn’s disease patients induces an inflammatory transcriptome in blood monocytes, including increased IL-6 expression, which is reduced by simultaneous blocking of TREM-1 and TNF.ConclusionsHigh intestinal TREM-1 expression, reflecting a high frequency of TREM-1+ immature macrophages and TREM-1+CD11b+ granulocytes, is linked to the deleterious inflammatory microenvironment in IBD patients. Therefore, blocking the TREM-1 pathway, especially simultaneously with anti-TNF therapy, has potential as a new IBD therapy.

ВЛИЯНИЕ ПРЕПАРАТОВ НА ОСНОВЕ ИНТЕРФЕРОНОВ НА ФОРМИРОВАНИЕ КЛЕТОЧНОГО ИММУНИТЕТА У НОВОРОЖДЕННЫХ ПОРОСЯТ

The article presents the results of a study of the corrective effect of drugs based on interferons on the cellular immunity of newborn piglets on an industrial pig breeding farm. In neonatal period, the immune system development in animals doesn’t reach functional maturity, and immunocompetent cells have low functional activity. In regulation of the immune system, interferons play a significant role in formation of the immune response, proliferation and differentiation of lymphocytes, as well as the activation of mononuclear phagocytes. In order to improve the body immune status, there’ve been designed species-specific drugs based on rIFNs with immunomodulatory properties. For the experiment, 3 groups of newborn piglets were selected. Piglets of experimental group I at the age of 3-5 days were injected intramuscularly with biferon-S at a dose of 0.1 ml/kg twice, with an interval of 24 hours, piglets of group II – once with prostimul at a dose of 0.1 ml/kg. Piglets of group III (control) were not treated with drugs. It has been established that the application of biferon-S, containing rpIFN–alpha and -gamma, and prostimul, containing recombinant type I cytokine and vitamins A, E and C, in the first days of piglets' life, promotes an increase in cellular immunity, the absolute and relative number of lymphocytes, Tlymphocytes, T-suppressors and T-helpers, the content of active phagocytes, their absorptive and metabolic activity, due to the presence of rpIFN in the drugs that rapidly induce the system of endogenous interferons, cellular and humoral immunity, and in prostimul –vitamins A, E and C, possessing antioxidant properties. A more significant corrective effect on cellular immunity has been exerted by biferon-S, containing not only interferon alpha, but also gamma, which is cytokine - a regulator of immune responses, an inducer of cellular immunity.

FUNCTIONAL ACTIVITY CHANGES OF THE MONONUCLEAR PHAGOCYTE SYSTEM IN PATIENTS WITH RAPIDLY PROGRESSIVE GENERALIZED PERIDONTITIS WITH PERIODONTAL MICROORGANISMS SENSITIVE AND RESISTANT TO DRUGS

Purpose. To reveal peculiarities of the mononuclear phagocyte functional activity in patients with rapidly progressive generalized periodontitis depending upon colonization of periodontal tissue by causative agents, sensitive and resistant to drugs, on the basis of studying activated blood monocytes, phagocytic activity of mononuclear phagocytes and production of the main classes of immunoglobulins, cytokine profile state. Material and methods. The investigation was carried out on 74 patients with rapidly progressive generalized periodontitis I-II and II-III severity, aged 35 to 50 years. Complex of the laboratory studies included immunophenotypic changes in the subpopulation composition of the mononuclear blood cells (CD3 +, CD4 +, CD8 +, CD14 +, CD16 +, CD25 +, HLA-DR and CD95+), phagocytic activity of neutrophils, level of cytokine production and synthesis of sIgA, IgA, IgG and IgM in the oral fluid. Results. On the basis of the conducted complex clinical-laboratory data it has been established that a significant decrease of the functional activity of the mononuclear phagocyte system stipulates the formation of the severe secondary deficiency of the cellular and humoral immunity in patients who are carries of the resistant strains of periodontal pathogenic agents of the rapidly progressive generalized periodontitis and moderate - at colonization of the periodontal complex with causative agents sensitive to drugs. The pathogenetic dependence of the drug sensitivity upon the nature of the disorders of the systemic and local humoral immunity has been shown: at the marked immunodeficiency the development of the bacterial resistance to drugs is possible, and preservation of the drug sensitivity to the causative agents of the rapidly progressive generalized periodontitis is associated with moderate disorders of anti-infectious mechanisms of the immune response. Conclusion. The assessment of the functional activity of the mononuclear phagocyte system, based on the study of the state of immunophenotypic changes in the subpopulation composition of mononuclear blood cells, phagocytic activity of monocytes, the content of immunoglobulins and cytokines in the oral fluid, gives valuable information to clarify the mechanisms of the development of various sensitivity of the periodontal-pathogenic flora of the periodontal tissue to protocol antibacterial therapy in the patients with rapidly progressive generalized periodontitis.

Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence.

As the prevalence of diabetes continues to climb, the number of individuals living with diabetic complications will reach an unprecedented magnitude. The emergence of new glucose-lowering agents - sodium-glucose cotransporter 2 inhibitors and incretin therapies - has markedly changed the treatment landscape of type 2 diabetes mellitus. In addition to effectively lowering glucose, incretin drugs, which include glucagon-like peptide 1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, can also reduce blood pressure, body weight, the risk of developing or worsening chronic kidney disease and/or atherosclerotic cardiovascular events, and the risk of death. Although kidney disease events have thus far been secondary outcomes in clinical trials, an ongoing phase III trial in patients with diabetic kidney disease will test the effect of a GLP1R agonist on a primary kidney disease outcome. Experimental data have identified the modulation of innate immunity and inflammation as plausible biological mechanisms underpinning the kidney-protective effects of incretin-based agents. These drugs block the mechanisms involved in the pathogenesis of kidney damage, including the activation of resident mononuclear phagocytes, tissue infiltration by non-resident inflammatory cells, and the production of pro-inflammatory cytokines and adhesion molecules. GLP1R agonists and DPP4 inhibitors might also attenuate oxidative stress, fibrosis and cellular apoptosis in the kidney.

Serum macrophage colony-stimulating factor levels in patients with essential hypertension after SARS-CoV-2 infection

Understanding changes in the cytokine-mediated mechanisms in immunopathogenesis of essential hypertension (EH) after COVID-19 poses a pressing scientific issue. SARS-CoV-2 exerts direct effects on macrophages with high probability altering regulatory M-CSF-VEGF-A-IL-34 axis, thereby accounting for change in cytokine-mediated patterns of hypertension progression. Immunopathogenesis of complications after SARS-CoV-2 infection and a role of M-CSF in EH pathogenesis justify study objective – to compare the serum M-CSF and VEGF-A, IL-34 levels in stage II EH patients prior to COVID-19 and one month after recovery to assess modality of altered M-CSF-mediated mechanisms behind hypertension progression. Four groups of patients were stratified depending on EH and clinical characteristics of COVID-19 (without/with pneumonia). Blood sampling was performed one month after COVID-19. The serum M-CSF and VEGF-A, IL-34 level was measured by using enzyme-linked immunosorbent assay. The data were statistically processed by using Stat Soft Statistica 13.5. Comparative analysis of serum M-CSF level in patients with stage II EH prior and after COVID-19 revealed that regardless of clinical course (with/without pneumonia) they were featured with higher levels of M-CSF one month after recovery (p 0.001) vs baseline level. The serum VEGF-A level in patients with stage II EH did not change in papallel with increased M-CSF (458 pg/ml or more) one month after SARS CoV 2 infection. However, M-CSF stimulated rise in serum VEGF-A level and accounted for formation of marked coronary collateral network prior to infection. A relationship between the increased serum M-CSF level (higher than 392 pg/ml) and elevated percentage of COVID-19 with pneumonia in patients with stage II EH prior to the infection might be related to the hypothesis about “a role of dysregulated activation of mononuclear phagocytes in development of lung tissue damage”. The data presented prove scientific and clinical value of assessing a role for M-CSF with respect to altered cytokine-mediated patterns of EH progression after COVID-19 recovery.

AN UNUSUAL CASE REPORT OF SARCOIDOSIS IN AN HIV PATIENT

SESSION TITLE: Fellows Diffuse Lung Disease Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Coexistence of sarcoidosis in HIV patient is a rare phenomenon and has been attributed to the impairment of immune system that may interfere with granuloma formation.(1) We present an unusual case report of sarcoidosis in HIV patient. CASE PRESENTATION: 58-year-old female with history of HIV on highly active antiretroviral therapy (HAART) (CD4 count: 746 and viral load <20/ml) presented with incidental basilar pulmonary nodules during work up for abdominal pain. Subsequent CT chest showed multiple nodular densities in all lung fields with hilar and mediastinal lymphadenopathy. She is lifetime nonsmoker and had no respiratory symptoms. PET-CT showed avid mediastinal lymph nodes and bone lesions. Bronchoscopy with EBUS guided TBNA was inconclusive with negative fungal and mycobacterial cultures. Thereafter, IR guided bone biopsy was pursued which revealed non-caseating ” naked ” granulomas. Diagnosis of sarcoidosis was established after excluding other granulomatous inflammation, infection, and malignancy. No treatment was initiated as the patient was asymptomatic. DISCUSSION: The introduction of HAART has led to sustained increase in CD4+ T lymphocyte cells, consequently leading to the development of so called “immune restoration disease”. Sarcoidosis is an immune mediated systemic disease resulting from exaggerated cellular immune response to a variety of antigens or self-antigens, in which T lymphocyte triggering, proliferation, and activation is sustained by the CD4+ type 1 (TH1) lymphocytes. TH1 cells produce IFN-?, IL-2, and TNF leading to attraction and activation of mononuclear phagocytes that induce granuloma formation. These immunological features are not clearly exhibited in coexistent sarcoidosis/HIV infection. Before HAART therapy, reports indicated a prevalence of lymphocytic alveolitis due to an increase in CD8 cells, with a very low CD4/CD8 ratio. In a retrospective cohort study, it was concluded that the development of sarcoidosis appears to depend on preservation or restoration of peripheral CD4+ lymphocyte count exceeding 200 cells/µl compared to alternative specific etiologies of granulomatous inflammation.(2) It is worth noting that in all reported clinical cases, sarcoidosis developed several months after HAART therapy compared to acute onset of other typical immune reconstitution syndromes.(1) The need to initiate steroid therapy, as in other immune reconstitution granulomatous processes, remains controversial and is based on patient’s symptoms. CONCLUSIONS: Our case highlights the importance of considering “immune restoration disease” including sarcoidosis and other granulomatous inflammation/infection in HIV patient on HAART therapy with abnormal chest imaging in addition to slow growing lymphoproliferative disorder. Reference #1: Sarcoidosis and HIV infection: a case report and a review of the literature, Postgrad Med J. 2003;79:535–38 Reference #2: Sarcoidosis Following HIV Infection, Chest 2003 Sep; 124 (3), 929–935 DISCLOSURES: No relevant relationships by Moises Cossio, source=Web Response No relevant relationships by Domingo Franco-Palacios, source=Web Response No relevant relationships by Kushagra Gupta, source=Web Response No relevant relationships by Shahzad Hussain, source=Web Response No relevant relationships by Venkateswara Kollipara, source=Web Response No relevant relationships by Toribiong Uchel, source=Web Response

Cell-intrinsic metabolic regulation of mononuclear phagocyte activation: Findings from the tip of the iceberg.

We have only recently started to appreciate the extent to which immune cell activation involves significant changes in cellular metabolism. We are now beginning to understand how commitment to specific metabolic pathways influences aspects of cellular biology that are the more usual focus of immunological studies, such as activation-induced changes in gene transcription, post-transcriptional regulation of transcription, post-translational modifications of proteins, cytokine secretion, etc. Here, we focus on metabolic reprogramming in mononuclear phagocytes downstream of stimulation with inflammatory signals (such as LPS and IFNγ) vs alternative activation signals (IL-4), with an emphasis on work on dendritic cells and macrophages from our laboratory, and related studies from others. We cover aspects of glycolysis and its branching pathways (glycogen synthesis, pentose phosphate, serine synthesis, hexose synthesis, and glycerol 3 phosphate shuttle), the tricarboxylic acid pathway, fatty acid synthesis and oxidation, and mitochondrial biology. Although our understanding of the metabolism of mononuclear phagocytes has progressed significantly over the last 10years, major challenges remain, including understanding the effects of tissue residence on metabolic programming related to cellular activation, and the translatability of findings from mouse to human biology.

Targeted Amino Acid Substitution Overcomes Scale-Up Challenges with the Human C5a-Derived Decapeptide Immunostimulant EP67.

EP67 is a second-generation, human C5a-derived decapeptide agonist of C5a receptor 1 (C5aR1/CD88) that selectively activates mononuclear phagocytes over neutrophils to potentiate protective innate and adaptive immune responses while potentially minimizing neutrophil-mediated toxicity. Pro7 and N-methyl-Leu8 (Me-Leu8) amino acid residues within EP67 likely induce backbone structural changes that increase potency and selective activation of mononuclear phagocytes over neutrophils versus first-generation EP54. The low coupling efficiency between Pro7 and Me-Leu8 and challenging purification by HPLC, however, greatly increase scale-up costs of EP67 for clinical use. Thus, the goal of this study was to determine whether replacing Pro7 and/or Me-Leu8 with large-scale amenable amino acid residues predicted to induce similar structural changes (cyclohexylalanine7 and/or leucine8) sufficiently preserves EP67 activity in primary human mononuclear phagocytes and neutrophils. We found that EP67 analogues had similar potency, efficacy, and selective activation of mononuclear phagocytes over neutrophils. Thus, replacing Pro7 and/or Me-Leu8 with large-scale amenable amino acid residues predicted to induce similar structural changes is a suitable strategy to overcome scale-up challenges with EP67.

Mononuclear Phagocyte Activation Is Associated With the Immunopathology of Psoriasis.

Psoriasis is a chronic, inflammatory disease affecting the skin and joints. The pathogenesis of this disease is associated with genetic, environmental and immunological factors, especially unbalanced T cell activation and improper keratinocyte differentiation. Psoriatic lesion infiltrate is composed of monocytes and T cells, and most studies have focused on the participation of T cells in the pathogenesis of this disease. Here we investigated the contribution of mononuclear phagocytes in the immunopathology observed in psoriatic patients. Significant increases in the levels of TNF, IL-1β, CXCL9, as well as the soluble forms of CD14 and CD163, were observed within the lesions of psoriatic patients compared to skin biopsies obtained from healthy individuals. Moreover, we found an association between the levels of CCL2, a monocyte attractant chemokine, and disease severity. In conclusion, our findings suggest a potential role for mononuclear phagocytes in the pathogenesis of psoriasis.

Predictive biomarkers for cognitive decline during progressive HIV infection.

Predictive biomarkers for cognitive decline during progressive HIV infection.