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Cellular & Molecular Immunology May 2024The overexpression of sialic acids on glycans, called hypersialylation, is a common alteration found in cancer cells. Sialylated glycans can enhance immune evasion by...
The overexpression of sialic acids on glycans, called hypersialylation, is a common alteration found in cancer cells. Sialylated glycans can enhance immune evasion by interacting with sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on tumor-infiltrating immune cells. Here, we investigated the effect of sialylated glycans and their interaction with Siglec receptors on myeloid-derived suppressor cells (MDSCs). We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors and are highly sialylated. In murine cancer models of emergency myelopoiesis, Siglec-E knockout in myeloid cells resulted in prolonged survival and increased tumor infiltration of activated T cells. Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation strongly reduced their suppressive potential. We further identified CCL2 as a mediator involved in T-cell suppression upon interaction between sialoglycans and Siglec receptors on MDSCs. Our results demonstrated that sialylated glycans inhibit anticancer immunity by modulating CCL2 expression.
Topics: Animals; Sialic Acid Binding Immunoglobulin-like Lectins; Polysaccharides; Myeloid-Derived Suppressor Cells; Humans; Chemokine CCL2; Mice; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes; Cell Line, Tumor; Lung Neoplasms; N-Acetylneuraminic Acid
PubMed: 38448555
DOI: 10.1038/s41423-024-01142-0 -
Basic Research in Cardiology Apr 2024Myocardial infarction (MI) induces the generation of proinflammatory Ly6C monocytes in the spleen and the recruitment of these cells to the myocardium. CD4 Foxp3 CD25...
Myocardial infarction (MI) induces the generation of proinflammatory Ly6C monocytes in the spleen and the recruitment of these cells to the myocardium. CD4 Foxp3 CD25 T-cells (Tregs) promote the healing process after myocardial infarction by engendering a pro-healing differentiation state in myocardial monocyte-derived macrophages. We aimed to study the effects of CD4 T-cells on splenic myelopoiesis and monocyte differentiation. We instigated MI in mice and found that MI-induced splenic myelopoiesis is abrogated in CD4 T-cell deficient animals. Conventional CD4 T-cells promoted myelopoiesis in vitro by cell-cell-contact and paracrine mechanisms, including interferon-gamma (IFN-γ) signalling. Depletion of regulatory T-cells enhanced myelopoiesis in vivo, as evidenced by increases in progenitor cell numbers and proliferative activity in the spleen 5 days after MI. The frequency of CD4 T-cells-producing factors that promote myelopoiesis increased within the spleen of Treg-depleted mice. Moreover, depletion of Tregs caused a proinflammatory bias in splenic Ly6C monocytes, which showed predominantly upregulated expression of IFN-γ responsive genes after MI. Our results indicate that conventional CD4 T-cells promote and Tregs attenuate splenic myelopoiesis and proinflammatory differentiation of monocytes.
Topics: Mice; Animals; Monocytes; Myelopoiesis; Spleen; Myocardial Infarction; T-Lymphocytes, Regulatory; Interferon-gamma; Mice, Inbred C57BL
PubMed: 38436707
DOI: 10.1007/s00395-024-01035-3 -
International Immunology Jun 2024Bone marrow is a dynamic organ composed of stem cells that constantly receive signals from stromal cells and other hematopoietic cells in the niches of the bone marrow...
Bone marrow is a dynamic organ composed of stem cells that constantly receive signals from stromal cells and other hematopoietic cells in the niches of the bone marrow to maintain hematopoiesis and generate immune cells. Perturbation of the bone marrow microenvironment by infection and inflammation affects hematopoiesis and may affect immune cell development. Little is known about the effect of malaria on the bone marrow stromal cells that govern the hematopoietic stem cell (HSC) niche. In this study, we demonstrate that the mesenchymal stromal CXCL12-abundant reticular (CAR) cell population is reduced during acute malaria infection. The reduction of CXCL12 and interleukin-7 signals in the bone marrow impairs the lymphopoietic niche, leading to the depletion of common lymphoid progenitors, B cell progenitors, and mature B cells, including plasma cells in the bone marrow. We found that interferon-γ (IFNγ) is responsible for the upregulation of Sca1 on CAR cells, yet the decline in CAR cell and B cell populations in the bone marrow is IFNγ-independent. In contrast to the decline in B cell populations, HSCs and multipotent progenitors increased with the expansion of myelopoiesis and erythropoiesis, indicating a bias in the differentiation of multipotent progenitors during malaria infection. These findings suggest that malaria may affect host immunity by modulating the bone marrow niche.
Topics: Animals; Chemokine CXCL12; Mice; Malaria; B-Lymphocytes; Bone Marrow; Mice, Inbred C57BL; Stem Cell Niche; Interferon-gamma; Hematopoietic Stem Cells
PubMed: 38430523
DOI: 10.1093/intimm/dxae012 -
Cell Mar 2024Neonates are highly susceptible to inflammation and infection. Here, we investigate how late fetal liver (FL) mouse hematopoietic stem and progenitor cells (HSPCs)...
Neonates are highly susceptible to inflammation and infection. Here, we investigate how late fetal liver (FL) mouse hematopoietic stem and progenitor cells (HSPCs) respond to inflammation, testing the hypothesis that deficits in the engagement of emergency myelopoiesis (EM) pathways limit neutrophil output and contribute to perinatal neutropenia. We show that fetal HSPCs have limited production of myeloid cells at steady state and fail to activate a classical adult-like EM transcriptional program. Moreover, we find that fetal HSPCs can respond to EM-inducing inflammatory stimuli in vitro but are restricted by maternal anti-inflammatory factors, primarily interleukin-10 (IL-10), from activating EM pathways in utero. Accordingly, we demonstrate that the loss of maternal IL-10 restores EM activation in fetal HSPCs but at the cost of fetal demise. These results reveal the evolutionary trade-off inherent in maternal anti-inflammatory responses that maintain pregnancy but render the fetus unresponsive to EM activation signals and susceptible to infection.
Topics: Animals; Mice; Pregnancy; Fetus; Hematopoiesis; Hematopoietic Stem Cells; Inflammation; Interleukin-10; Myelopoiesis; Animals, Newborn; Female
PubMed: 38428422
DOI: 10.1016/j.cell.2024.02.002 -
International Immunopharmacology Mar 2024The immune escape stage in cancer immunoediting is a pivotal feature, transitioning immune-controlled tumor dormancy to progression, and augmenting invasion and...
The immune escape stage in cancer immunoediting is a pivotal feature, transitioning immune-controlled tumor dormancy to progression, and augmenting invasion and metastasis. Tumors employ diverse mechanisms for immune escape, with generating immunosuppressive cells from skewed hematopoiesis being a crucial mechanism. This led us to suggest that tumor cells with immune escape properties produce factors that induce dysregulations in hematopoiesis. In support of this suggestion, this study found that mice bearing advanced-stage tumors exhibited dysregulated hematopoiesis characterized by the development of splenomegaly, anemia, extramedullary hematopoiesis, production of immunosuppressive mediators, and expanded medullary myelopoiesis. Further ex vivo studies exhibited that conditioned medium derived from EL4lu2 cells could mediate the expansion of myeloid derived suppressor cells (MDSCs) in bone marrow cell cultures. The protein array profiling results revealed the presence of elevated levels of osteopontin (OPN), prostaglandin E2 (PGE2) and interleukin 17 (IL-17) in the culture medium derived from EL4luc2 cells. Accordingly, substantial levels of these factors were also detected in the sera of mice bearing EL4luc2 tumors. Among these factors, only PGE2 alone could increase the number of MDSCs in the BM cell cultures. This effect of PGE2 was significantly potentiated by the presence of OPN but not IL-17. Finally, in vitro treatment of EL4luc2 cells with pioglitazone, a modulator of OPN and cyclooxygenase 2 (COX-2) resulted in a significant reduction in cell proliferation in EL4luc2 cells. Our findings highlight the significant role played by tumor cell-derived OPN and PGE2 in fostering the expansion of medullary MDSCs and in promoting tumor cell proliferation. Furthermore, these intertwined cancer processes could be key targets for pioglitazone intervention.
Topics: Animals; Mice; Dinoprostone; Myeloid-Derived Suppressor Cells; Osteopontin; Pioglitazone; Tumor Escape
PubMed: 38364741
DOI: 10.1016/j.intimp.2024.111584 -
IScience Mar 2024Fungal β-glucans are major drivers of trained immunity which increases long-term protection against secondary infections. Heterogeneity in β-glucan source, structure,...
Fungal β-glucans are major drivers of trained immunity which increases long-term protection against secondary infections. Heterogeneity in β-glucan source, structure, and solubility alters interaction with the phagocytic receptor Dectin-1 and could impact strategies to improve trained immunity in humans. Using a panel of diverse β-glucans, we describe the ability of a specific yeast-derived whole-glucan particle (WGP) to reprogram metabolism and thereby drive trained immunity in human monocyte-derived macrophages and mice bone marrow . Presentation of pure, non-soluble, non-aggregated WGPs led to the formation of the Dectin-1 phagocytic synapse with subsequent lysosomal mTOR activation, metabolic reprogramming, and epigenetic rewiring. Intraperitoneal or oral administration of WGP drove bone marrow myelopoiesis and improved mature macrophage responses, pointing to therapeutic and food-based strategies to drive trained immunity. Thus, the investment of a cell in a trained response relies on specific recognition of β-glucans presented on intact microbial particles through stimulation of the Dectin-1 phagocytic response.
PubMed: 38361630
DOI: 10.1016/j.isci.2024.109030 -
Annals of African Medicine 2023Aplastic anemia (AA) is an uncommon condition characterized by pancytopenia and hypocellular bone marrow. Interleukin (IL)-6 and IL-8 have been shown to inhibit...
BACKGROUND
Aplastic anemia (AA) is an uncommon condition characterized by pancytopenia and hypocellular bone marrow. Interleukin (IL)-6 and IL-8 have been shown to inhibit myelopoiesis and are major mediators of tissue damage. The primary goal of this study was to determine the IL-6 and IL-8 levels in children with AA, as well as their relationship to illness severity and immunosuppressive medication response.
MATERIALS AND METHODS
The IL-6 and IL-8 levels were tested in 50 children aged 3-18 years who had AA. As controls, 50 healthy age and sex matched individuals were used. A sandwich enzyme-linked immunosorbent assay kit (solid-phase) was used to measure IL-6 and IL-8 levels quantitatively. The concentrations of IL-6 and IL-8 in pg/mL were used to represent the results. Immunosuppressive medication was given to the patients in accordance with the British Committee for Standards in Haematology Guidelines 2009.
RESULTS
The patients' average age was 11.3 ± 3.7 years. Patients with AA had significantly higher IL-6 and IL-8 levels than controls (278.88 ± 216.03 vs. 4.51 ± 3.26; P < 0.001) and (120.28 ± 94.98 vs. 1.79 ± 0.78; P < 0.001), respectively. The IL-6 and IL-8 levels were also investigated with respect to AA severity, with statistically significant differences (P < 0.01) between different grading strata. Patients with very severe AA (VSAA) had the highest IL-6 levels (499.52 ± 66.19), followed by severe AA (SAA) (201.28 ± 157.77) and non-SAA (NSAA) (22.62 ± 14.63). For IL-8 levels, a similar trend (P < 0.01) was detected, with values of 209.81 ± 38.85, 92.12 ± 78.0, and 9.29 ± 10.68 for VSAA, SAA, and NSAA, respectively. After 6 months of immunosuppressive treatment (IST), mean levels of IL-6 and IL-8 in responders and nonresponders were again assessed. The mean IL-6 level in the responders' group (46.50 ± 45.41) was significantly lower, when compared to the nonresponders' group (145.76 ± 116.32) (P < 0.001). Similarly, the mean IL-8 level in the responder's group (33.57 ± 27.14) was significantly lower, compared to the nonresponder's group (97.49 ± 69.00) (P < 0.001).
CONCLUSIONS
Children with AA had higher IL-6 and IL-8 levels than normal age- and sex-matched controls. Increased levels were linked to the severity of the condition, suggesting that IL may have a role in AA. IL levels can be monitored in AA patients during IST, which can assist in predicting response to IST.
Topics: Child; Humans; Adolescent; Anemia, Aplastic; Interleukin-6; Interleukin-8; Treatment Outcome; Immunosuppressive Agents; Immunosuppression Therapy; Patient Acuity
PubMed: 38358144
DOI: 10.4103/aam.aam_106_22 -
Open Biology Feb 2024Transient abnormal myelopoiesis (TAM) is a Down syndrome-related pre-leukaemic condition characterized by somatic mutations in the haematopoietic transcription factor...
Transient abnormal myelopoiesis (TAM) is a Down syndrome-related pre-leukaemic condition characterized by somatic mutations in the haematopoietic transcription factor GATA-1 that result in exclusive production of its shorter isoform (GATA-1). Given the common hallmark of altered miRNA expression profiles in haematological malignancies and the pro-leukaemic role of GATA-1, we aimed to search for miRNAs potentially able to modulate the expression of GATA-1 isoforms. Starting from an prediction of miRNA binding sites in the GATA-1 transcript, miR-1202 came into our sight as potential regulator of GATA-1 expression. Expression studies in K562 cells revealed that miR-1202 directly targets GATA-1, negatively regulates its expression, impairs GATA-1 production, reduces cell proliferation, and increases apoptosis sensitivity. Furthermore, data from TAM and myeloid leukaemia patients provided substantial support to our study by showing that miR-1202 down-modulation is accompanied by increased GATA-1 levels, with more marked effects on GATA-1. These findings indicate that miR-1202 acts as an anti-oncomiR in myeloid cells and may impact leukaemogenesis at least in part by down-modulating GATA-1 levels.
Topics: Humans; Down Syndrome; Leukemia, Myeloid; Leukemoid Reaction; MicroRNAs
PubMed: 38350611
DOI: 10.1098/rsob.230319 -
Nature Cardiovascular Research Dec 2023After myocardial infarction (MI), emergency hematopoiesis produces inflammatory myeloid cells that accelerate atherosclerosis and promote heart failure. Since the...
After myocardial infarction (MI), emergency hematopoiesis produces inflammatory myeloid cells that accelerate atherosclerosis and promote heart failure. Since the balance between glycolysis and mitochondrial metabolism regulates hematopoietic stem cell homeostasis, metabolic cues may influence emergency myelopoiesis. Here, we show in humans and female mice that hematopoietic progenitor cells increase fatty acid metabolism after MI. Blockade of fatty acid oxidation by deleting carnitine palmitoyltransferase () in hematopoietic cells of mice limited hematopoietic progenitor proliferation and myeloid cell expansion after MI. We also observed reduced bone marrow adiposity in humans, pigs and mice following MI. Inhibiting lipolysis in adipocytes using mice or local depletion of bone marrow adipocytes in mice also curbed emergency hematopoiesis. Furthermore, systemic and regional sympathectomy prevented bone marrow adipocyte shrinkage after MI. These data establish a critical role for fatty acid metabolism in post-MI emergency hematopoiesis.
PubMed: 38344689
DOI: 10.1038/s44161-023-00388-7 -
ACS Nano Mar 2024Nanoparticles have been employed to elucidate the innate immune cell biology and trace cells accumulating at inflammation sites. Inflammation prompts innate immune...
Nanoparticles have been employed to elucidate the innate immune cell biology and trace cells accumulating at inflammation sites. Inflammation prompts innate immune cells, the initial responders, to undergo rapid turnover and replenishment within the hematopoietic bone marrow. Yet, we currently lack a precise understanding of how inflammation affects cellular nanoparticle uptake at the level of progenitors of innate immune cells in the hematopoietic marrow. To bridge this gap, we aimed to develop imaging tools to explore the uptake dynamics of fluorescently labeled cross-linked iron oxide nanoparticles in the bone marrow niche under varying degrees of inflammation. The inflammatory models included mice that received intramuscular lipopolysaccharide injections to induce moderate inflammation and streptozotocin-induced diabetic mice with additional intramuscular lipopolysaccharide injections to intensify inflammation. In vivo magnetic resonance imaging (MRI) and fluorescence imaging revealed an elevated level of nanoparticle uptake at the bone marrow as the levels of inflammation increased. The heightened uptake of nanoparticles within the inflamed marrow was attributed to enhanced permeability and retention with increased nanoparticle intake by hematopoietic progenitor cells. Moreover, intravital microscopy showed increased colocalization of nanoparticles within slowly patrolling monocytes in these inflamed hematopoietic marrow niches. Our discoveries unveil a previously unknown role of the inflamed hematopoietic marrow in enhanced storage and rapid deployment of nanoparticles, which can specifically target innate immune cells at their production site during inflammation. These insights underscore the critical function of the hematopoietic bone marrow in distributing iron nanoparticles to innate immune cells during inflammation. Our findings offer diagnostic and prognostic value, identifying the hematopoietic bone marrow as an imaging biomarker for early detection in inflammation imaging, advancing personalized clinical care.
Topics: Animals; Mice; Bone Marrow; Lipopolysaccharides; Diabetes Mellitus, Experimental; Inflammation; Nanoparticles
PubMed: 38343099
DOI: 10.1021/acsnano.3c11201