scholarly journals Leptin Receptor q223r Polymorphism Influences Clostridioides difficile Infection-Induced Neutrophil CXCR2 Expression in an Interleukin-1β Dependent Manner

2021 ◽  
Vol 11 ◽  
Author(s):  
Olivia Horrigan ◽  
Shinsmon Jose ◽  
Anindita Mukherjee ◽  
Divya Sharma ◽  
Alexander Huber ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Leptin Receptor ◽  
Innate Immune ◽  
Dependent Manner ◽  
Biological Mechanisms ◽  
Colonic Tissue ◽  
Host Genetics ◽  
Cxcr2 Expression ◽  
Clostridioides Difficile ◽  
Blood Neutrophils

Neutrophils are key first-responders in the innate immune response to C. difficile infection (CDI) and play a central role in disease pathogenesis. Studies have clearly shown that tissue neutrophil numbers need to be tightly regulated for optimal CDI outcomes: while excessive colonic neutrophilia is associated with severe CDI, neutrophil depletion also results in worse outcomes. However, the biological mechanisms that control CDI-induced neutrophilia remain poorly defined. C-X-C chemokine receptor 2 (CXCR2) is a chemotactic receptor that is critical in neutrophil mobilization from bone marrow to blood and tissue sites. We have previously reported that a single nucleotide polymorphism (SNP) in leptin receptor (LEPR), present in up to 50% of people, influenced CDI-induced neutrophil CXCR2 expression and tissue neutrophilia. Homozygosity for mutant LEPR (i.e. RR genotype) was associated with higher CXCR2 expression and more tissue neutrophils. Here, we investigated the biological mechanisms that regulate neutrophil CXCR2 expression after CDI, and the influence of host genetics on this process. Our data reveal that: a) CXCR2 plays a key role in CDI-induced neutrophil extravasation from blood to colonic tissue; b) plasma from C. difficile-infected mice upregulated CXCR2 on bone marrow neutrophils; c) plasma from C. difficile-infected RR mice induced a higher magnitude of CXCR2 upregulation and had more IL-1β; and d) IL-1β neutralization reduced CXCR2 expression on bone marrow and blood neutrophils and their subsequent accrual to colonic tissue. In sum, our data indicate that IL-1β is a key molecular mediator that communicates between gastro-intestinal tract (i.e. site of CDI) and bone marrow (i.e. primary neutrophil reservoir) and regulates the intensity of CDI-induced tissue neutrophilia by modulating CXCR2 expression. Further, our studies highlight the importance of host genetics in affecting these innate immune responses and provide novel insights into the mechanisms by which a common SNP influences CDI-induced neutrophilia.

Surfactant protein D enhances bacterial antigen presentation by bone marrow-derived dendritic cells

2001 ◽  
Vol 281 (6) ◽  
pp. L1453-L1463 ◽  
Author(s):  
Karen G. Brinker ◽  
Emily Martin ◽  
Paul Borron ◽  
Elahe Mostaghel ◽  
Carolyn Doyle ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Dendritic Cells ◽  
Antigen Presentation ◽  
Surfactant Protein ◽  
Innate Immune ◽  
Surfactant Protein D ◽  
Mouse Bone Marrow ◽  
Bacterial Antigen ◽  
Dependent Manner

Surfactant protein (SP) D functions as a soluble pattern recognition molecule to mediate the clearance of pathogens by phagocytes in the innate immune response. We hypothesize that SP-D may also interact with dendritic cells, the most potent antigen presenting cell, to enhance uptake and presentation of bacterial antigens. Using mouse bone marrow-derived dendritic cells, we show that SP-D binds to immature dendritic cells in a dose-, carbohydrate-, and calcium-dependent manner, whereas SP-D binding to mature dendritic cells is reduced. SP-D also binds to Escherichia coli HB101 and enhances its association with dendritic cells. Additionally, SP-D enhances the antigen presentation of an ovalbumin fusion protein expressed in E. coli HB101 to ovalbumin-specific major histocompatibility complex class II T cell hybridomas. The enhancement of antigen presentation by SP-D is dose dependent and is not shared by other collectin-like proteins tested. These studies demonstrate that SP-D augments antigen presentation by dendritic cells and suggest that innate immune molecules such as SP-D may help initiate an adaptive immune response for the purpose of resolving an infection.

Abstract 17039: Neutrophil Subset in Blood Contributes to Acute Oxidant Signals in the Bone Marrow, Which Regulate Innate Immune Responses After Ischemic Tissue Damage

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Muthusamy Thiruppathi ◽  
Pijus Barman ◽  
Milie Fang ◽  
Timothy Koh ◽  
Norifumi Urao
Keyword(s):  
Bone Marrow ◽  
Immune Responses ◽  
Progenitor Cells ◽  
Limb Ischemia ◽  
Innate Immune ◽  
Ischemic Damage ◽  
Innate Immune Responses ◽  
Ischemic Tissue ◽  
Blood Neutrophils ◽  
Tissue Recovery

Blood neutrophils are short-lived and have distinct subsets. Aged (senescent) neutrophils are cleared by macrophages in multiple organs including bone marrow (BM), at least, in the steady state. It is unknown, after ischemic tissue damage, how these aged-type neutrophils regulate bone marrow microenvironment and impact on downstream bone marrow responses. In a mouse model of critical limb ischemia, we found that CD62L lo aged-type neutrophils that return to the BM, measured by in vivo circulating cell-labeling, are increased (2.1-fold) after acute limb ischemia, which is corresponded with acute increase in CXCR4, a major chemokine receptor promoting BM returning of blood neutrophils (31%). Interestingly, neutrophil uptake by macrophages is reduced (by 76%) in the BM after limb ischemia, suggesting increased retention of blood-derived CD62L lo neutrophils in BM microenvironment after ischemia. We also found, in the BM, that blood-derived neutrophils have higher reactive oxygen species (ROS) than other neutrophils (61% in MFI) and that limb ischemia indeed increases ROS (34%) and oxidized lipid microparticles (61%) in BM plasma in a Nox2 NADPH oxidase-dependent manner. These suggest that increased returning and retention of blood-derived CD62L lo neutrophils in the BM may contribute to oxidant signals in the BM after limb ischemia. Indeed, using aged neutrophils generated ex vivo and adoptive transfer of these cells, we found that aged neutrophils modulate BM innate immune responses after limb ischemia through ROS—reduced activation of hematopoietic stem progenitor cells (50%); increased acute activation of myeloid progenitor cells (4%); and increased acute but inhibited later Ly6C hi inflammatory monocytes/macrophages in the ischemic tissue (72% and 45%, respectively)—resulting in improved tissue recovery from ischemic damage (2.3-fold). In summary, an aged-type neutrophil subset in blood contributes to acute oxidant signals in the BM, which coordinate innate immune responses to promote tissue recovery from ischemic damage.

scholarly journals Phagocytosis and activation of bone marrow‐derived macrophages by Plasmodium falciparum gametocytes

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Yolanda Corbett ◽  
Silvia Parapini ◽  
Federica Perego ◽  
Valeria Messina ◽  
Serena Delbue ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Bone Marrow ◽  
Plasmodium Falciparum ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Murine Bone Marrow ◽  
Inflammatory Protein ◽  
Life Cycle Stages ◽  
Cytokine Levels ◽  
Necrosis Factor

Abstract Background The innate immune response against various life cycle stages of the malaria parasite plays an important role in protection against the disease and regulation of its severity. Phagocytosis of asexual erythrocytic stages is well documented, but little and contrasting results are available about phagocytic clearance of sexual stages, the gametocytes, which are responsible for the transmission of the parasites from humans to mosquitoes. Similarly, activation of host macrophages by gametocytes has not yet been carefully addressed. Methods Phagocytosis of early or late Plasmodium falciparum gametocytes was evaluated through methanol fixed cytospin preparations of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated for 2 h with P. falciparum and stained with Giemsa, and it was confirmed through a standardized bioluminescent method using the transgenic P. falciparum 3D7elo1-pfs16-CBG99 strain. Activation was evaluated by measuring nitric oxide or cytokine levels in the supernatants of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated with early or late gametocytes. Results The results showed that murine bone marrow-derived macrophages can phagocytose both early and late gametocytes, but only the latter were able to induce the production of inflammatory mediators, specifically nitric oxide and the cytokines tumour necrosis factor and macrophage inflammatory protein 2. Conclusions These results support the hypothesis that developing gametocytes interact in different ways with innate immune cells of the host. Moreover, the present study proposes that early and late gametocytes act differently as targets for innate immune responses.

scholarly journals Elevating body temperature enhances hematopoiesis and neutrophil recovery after total body irradiation in an IL-1–, IL-17–, and G-CSF–dependent manner

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2600-2609 ◽  
Author(s):  
Maegan L. Capitano ◽  
Michael J. Nemeth ◽  
Thomas A. Mace ◽  
Christi Salisbury-Ruf ◽  
Brahm H. Segal ◽  
...  
Keyword(s):  
Heat Treatment ◽  
Bone Marrow ◽  
Body Temperature ◽  
Total Body Irradiation ◽  
Dependent Manner ◽  
Intestinal Tissue ◽  
Hematopoietic Stem ◽  
Neutrophil Recovery ◽  
Total Body ◽  
The Impact

Abstract Neutropenia is a common side effect of cytotoxic chemotherapy and radiation, increasing the risk of infection in these patients. Here we examined the impact of body temperature on neutrophil recovery in the blood and bone marrow after total body irradiation (TBI). Mice were exposed to either 3 or 6 Gy TBI followed by a mild heat treatment that temporarily raised core body temperature to approximately 39.5°C. Neutrophil recovery was then compared with control mice that received either TBI alone heat treatment alone. Mice that received both TBI and heat treatment exhibited a significant increase in the rate of neutrophil recovery in the blood and an increase in the number of marrow hematopoietic stem cells and neutrophil progenitors compared with that seen in mice that received either TBI or heat alone. The combination treatment also increased G-CSF concentrations in the serum, bone marrow, and intestinal tissue and IL-17, IL-1β, and IL-1α concentrations in the intestinal tissue after TBI. Neutralizing G-CSF or inhibiting IL-17 or IL-1 signaling significantly blocked the thermally mediated increase in neutrophil numbers. These findings suggest that a physiologically relevant increase in body temperature can accelerate recovery from neutropenia after TBI through a G-CSF–, IL-17–, and IL-1–dependent mechanism.

Granulocytopenia Associated With Thymoma in a Domestic Shorthaired Cat

2008 ◽  
Vol 44 (4) ◽  
pp. 210-217 ◽  
Author(s):  
Janean L. Fidel ◽  
Indira S. Pargass ◽  
Michael J. Dark ◽  
Shannon P. Holmes
Keyword(s):  
Bone Marrow ◽  
Radiation Therapy ◽  
Immune Suppression ◽  
Bone Marrow Examination ◽  
Coarse Fraction ◽  
External Beam ◽  
Mass Treatment ◽  
Left Shift ◽  
Immune Mediated ◽  
Blood Neutrophils

A 5-year-old, spayed female cat was referred because of a mass in the cranial mediastinum noted on thoracic radiographs. A thymoma was diagnosed following ultrasound and biopsy of the mass. Treatment was initiated with coarse-fraction radiation therapy using external-beam therapy (four fractions of 5 Gy). The mass responded, but granulocytopenia developed. Bone marrow examination showed a myeloid to erythroid ratio of approximately 1:1, with a left shift within the myeloid line. These findings, as well as the lack of toxic changes within the peripheral blood neutrophils, suggested immune-mediated destruction of peripheral granulocytes. Immune suppression with prednisone and cyclosporine was instituted. After 7 weeks, the neutrophil count returned to normal. The tumor was removed, and cyclosporine was reduced and eventually discontinued 3 weeks postsurgery.

scholarly journals Masking of β(1-3)-Glucan in the Cell Wall of Candida albicans from Detection by Innate Immune Cells Depends on Phosphatidylserine

2014 ◽  
Vol 82 (10) ◽  
pp. 4405-4413 ◽  
Author(s):  
Sarah E. Davis ◽  
Alex Hopke ◽  
Steven C. Minkin ◽  
Anthony E. Montedonico ◽  
Robert T. Wheeler ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
De Novo ◽  
Invasive Disease ◽  
Innate Immune ◽  
Dependent Manner ◽  
Content Type ◽  
Immune Effector ◽  
Host Interactions ◽  
Innate Immune Effector

ABSTRACTThe virulence ofCandida albicansin a mouse model of invasive candidiasis is dependent on the phospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE). Disruption of the PS synthase geneCHO1(i.e.,cho1Δ/Δ) eliminates PS and blocks thede novopathway for PE biosynthesis. In addition, thecho1Δ/Δ mutant's ability to cause invasive disease is severely compromised. Thecho1Δ/Δ mutant also exhibits cell wall defects, and in this study, it was determined that loss of PS results in decreased masking of cell wall β(1-3)-glucan from the immune system. In wild-typeC. albicans, the outer mannan layer of the wall masks the inner layer of β(1-3)-glucan from exposure and detection by innate immune effector molecules like the C-type signaling lectin Dectin-1, which is found on macrophages, neutrophils, and dendritic cells. Thecho1Δ/Δ mutant exhibits increases in exposure of β(1-3)-glucan, which leads to greater binding by Dectin-1 in both yeast and hyphal forms. The unmasking of β(1-3)-glucan also results in increased elicitation of TNF-α from macrophages in a Dectin-1-dependent manner. The role of phospholipids in fungal pathogenesis is an emerging field, and this is the first study showing that loss of PS inC. albicansresults in decreased masking of β(1-3)-glucan, which may contribute to our understanding of fungus-host interactions.

scholarly journals β-Glucan enhances complement-mediated hematopoietic recovery after bone marrow injury

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 835-840 ◽  
Author(s):  
Daniel E. Cramer ◽  
Daniel J. Allendorf ◽  
Jarek T. Baran ◽  
Richard Hansen ◽  
Jose Marroquin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mouse Serum ◽  
Complement Receptor ◽  
Dependent Manner ◽  
Complement Receptor 3 ◽  
Total Body ◽  
Stimulating Factor ◽  
Sublethal Irradiation ◽  
Classic Pathway

AbstractMyelotoxic injury in the bone marrow (BM) as a consequence of total body irradiation (TBI) or granulocyte colony-stimulating factor (G-CSF) mobilization results in the deposition of iC3b on BM stroma (stroma-iC3b). In the present study, we have examined how stroma-iC3b interacts with hematopoietic progenitor cells (HPCs) and the role of complement (C) and complement receptor 3 (CR3) in BM injury/repair. We demonstrate here that stroma-iC3b tethers HPCs via the inserted (I) domain of HPC complement receptor 3 (CR3, CD11b/CD18, Mac-1). Following irradiation, stroma-iC3b was observed in the presence of purified IgM and normal mouse serum (NMS), but not serum from Rag-2-/- mice, implicating a role for antibody (Ab) and the classic pathway of C activation. Furthermore, a novel role for soluble yeast β-glucan, a ligand for the CR3 lectin-like domain (LLD), in the priming of CR3+ HPC is suggested. Soluble yeast β-glucan could enhance the proliferation of tethered HPCs, promote leukocyte recovery following sublethal irradiation, and increase the survival of lethally irradiated animals following allogeneic HPC transplantation in a CR3-dependent manner. Taken together, these observations suggest a novel role for C, CR3, and β-glucan in the restoration of hematopoiesis following injury. (Blood. 2006;107:835-840)

scholarly journals Ligand-dependent repression of the erythroid transcription factor GATA-1 by the estrogen receptor.

1995 ◽  
Vol 15 (6) ◽  
pp. 3147-3153 ◽  
Author(s):  
G A Blobel ◽  
C A Sieff ◽  
S H Orkin
Keyword(s):  
Bone Marrow ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Erythroid Cell ◽  
High Dose ◽  
Dependent Manner ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

High-dose estrogen administration induces anemia in mammals. In chickens, estrogens stimulate outgrowth of bone marrow-derived erythroid progenitor cells and delay their maturation. This delay is associated with down-regulation of many erythroid cell-specific genes, including alpha- and beta-globin, band 3, band 4.1, and the erythroid cell-specific histone H5. We show here that estrogens also reduce the number of erythroid progenitor cells in primary human bone marrow cultures. To address potential mechanisms by which estrogens suppress erythropoiesis, we have examined their effects on GATA-1, an erythroid transcription factor that participates in the regulation of the majority of erythroid cell-specific genes and is necessary for full maturation of erythrocytes. We demonstrate that the transcriptional activity of GATA-1 is strongly repressed by the estrogen receptor (ER) in a ligand-dependent manner and that this repression is reversible in the presence of 4-hydroxytamoxifen. ER-mediated repression of GATA-1 activity occurs on an artificial promoter containing a single GATA-binding site, as well as in the context of an intact promoter which is normally regulated by GATA-1. GATA-1 and ER bind to each other in vitro in the absence of DNA. In coimmunoprecipitation experiments using transfected COS cells, GATA-1 and ER associate in a ligand-dependent manner. Mapping experiments indicate that GATA-1 and the ER form at least two contacts, which involve the finger region and the N-terminal activation domain of GATA-1. We speculate that estrogens exert effects on erythropoiesis by modulating GATA-1 activity through protein-protein interaction with the ER. Interference with GATA-binding proteins may be one mechanism by which steroid hormones modulate cellular differentiation.

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