scholarly journals Macrophages in the uterus are functionally specialised and continually replenished from the circulation

2021 ◽  
Author(s):  
Nicholas A. Scott ◽  
Lamiya Mohiyiddeen ◽  
Livia Lacerda Mariano ◽  
Peter T. Ruane ◽  
John D. Aplin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Reproductive Cycle ◽  
Alternative Activation ◽  
Tissue Remodelling ◽  
Tissue Integrity ◽  
Mucosal Tissues ◽  
Monocytes And Macrophages ◽  
Differential Responses ◽  
Alternatively Activated

ABSTRACTMacrophages are innate immune cells that fight infection but also regulate tissue regeneration and remodelling. In the uterus, although tissue remodelling is essential for establishment and maintenance of pregnancy, the specialisation of macrophages is not well characterised compared to other mucosal tissues. Here we show that uterine macrophages are functionally specialised, expressing multiple markers of alternative activation associated with tissue remodelling and repair, and responding more highly to the type 2 cytokine IL-4 than other mucosal tissue macrophages. Uterine macrophages were continuously replenished from circulating bone marrow-derived CCR2+ monocytes that fluctuated dramatically in number throughout the reproductive cycle, and had properties distinct from the macrophages that they became, including differential responses to microbial stimulation. Importantly, many of these properties of uterine monocytes and macrophages were conserved between mice and humans. These findings further our understanding of immune regulation of uterine tissue integrity and have important implications for differences in immune responses to infections at different phases of the reproductive cycle.SUMMARYUterine macrophages are specialised, alternatively activated cells that are replenished from circulating bone marrow-derived monocytes. Monocyte and macrophage properties fluctuate markedly throughout the reproductive cycle, with many features conserved between mice and humans, and exhibiting differential responses to microbial stimulation.

scholarly journals Induction of IL-4Rα–dependent microRNAs identifies PI3K/Akt signaling as essential for IL-4–driven murine macrophage proliferation in vivo

Blood ◽  
2012 ◽  
Vol 120 (11) ◽  
pp. 2307-2316 ◽  
Author(s):  
Dominik Rückerl ◽  
Stephen J. Jenkins ◽  
Nouf N. Laqtom ◽  
Iain J. Gallagher ◽  
Tara E. Sutherland ◽  
...  
Keyword(s):  
Akt Signaling ◽  
Alternative Activation ◽  
In Vivo Model ◽  
Akt Signaling Pathway ◽  
Microrna Profile ◽  
Chemical Inhibition ◽  
Alternatively Activated

Abstract Macrophage (MΦ) activation must be tightly controlled to preclude overzealous responses that cause self-damage. MicroRNAs promote classical MΦ activation by blocking antiinflammatory signals and transcription factors but also can prevent excessive TLR signaling. In contrast, the microRNA profile associated with alternatively activated MΦ and their role in regulating wound healing or antihelminthic responses has not been described. By using an in vivo model of alternative activation in which adult Brugia malayi nematodes are implanted surgically in the peritoneal cavity of mice, we identified differential expression of miR-125b-5p, miR-146a-5p, miR-199b-5p, and miR-378-3p in helminth-induced MΦ. In vitro experiments demonstrated that miR-378-3p was specifically induced by IL-4 and revealed the IL-4–receptor/PI3K/Akt-signaling pathway as a target. Chemical inhibition of this pathway showed that intact Akt signaling is an important enhancement factor for alternative activation in vitro and in vivo and is essential for IL-4–driven MΦ proliferation in vivo. Thus, identification of miR-378-3p as an IL-4Rα–induced microRNA led to the discovery that Akt regulates the newly discovered mechanism of IL-4–driven macrophage proliferation. Together, the data suggest that negative regulation of Akt signaling via microRNAs might play a central role in limiting MΦ expansion and alternative activation during type 2 inflammatory settings.

Anti-Hypertensive Potential and Epigenetics of Angiotensin II type 2 Receptor (AT2R)

2020 ◽  
Vol 16 ◽  
Author(s):  
Mayank Chaudhary
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Renin Angiotensin System ◽  
Blood Pressure Regulation ◽  
Biologically Active ◽  
Pressure Regulation ◽  
Tissue Remodelling ◽  
Critical Pathway

Background:: Renin angiotensin system (RAS) is a critical pathway involved in blood pressure regulation. Octapeptide, angiotensin II (Ang aII), is biologically active compound of RAS pathway which mediates its action by binding to either angiotensin II type 1 receptor (AT1R) or angiotensin II type 2 receptor (AT2R). Binding of Ang II to AT1R facilitates blood pressure regulation whereas AT2R is primarily involved in wound healing and tissue remodelling. Objective:: Recent studies have highlighted additional role of AT2R to counter balance detrimental effects of AT1R. Activation of angiotensin II type 2 receptor using AT2R agonist has shown effect on natriuresis and release of nitric oxide. Additionally, AT2R activation has been found to inhibit angiotensin converting enzyme (ACE) and enhance angiotensin receptor blocker (ARB) activity. These findings highlight the potential of AT2R as novel therapeutic target against hypertension. Conclusion:: The potential role of AT2R highlights the importance of exploring additional mechanisms that might be crucial for AT2R expression. Epigenetic mechanisms including DNA methylation and histone modification have been explored vastly with relation to cancer but role of such mechanisms on expression of AT2R has recently gained interest.

scholarly journals Fructose reprogrammes glutamine-dependent oxidative metabolism to support LPS-induced inflammation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nicholas Jones ◽  
Julianna Blagih ◽  
Fabio Zani ◽  
April Rees ◽  
David G. Hill ◽  
...  
Keyword(s):  
Oxidative Metabolism ◽  
Mononuclear Phagocytes ◽  
Alcoholic Fatty Liver ◽  
Lps Challenge ◽  
Fructose Intake ◽  
Mouse Macrophages ◽  
Dietary Fructose ◽  
Monocytes And Macrophages ◽  
Developed World

AbstractFructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease. Currently, our understanding of the metabolic and mechanistic implications for immune cells, such as monocytes and macrophages, exposed to elevated levels of dietary fructose is limited. Here, we show that fructose reprograms cellular metabolic pathways to favour glutaminolysis and oxidative metabolism, which are required to support increased inflammatory cytokine production in both LPS-treated human monocytes and mouse macrophages. A fructose-dependent increase in mTORC1 activity drives translation of pro-inflammatory cytokines in response to LPS. LPS-stimulated monocytes treated with fructose rely heavily on oxidative metabolism and have reduced flexibility in response to both glycolytic and mitochondrial inhibition, suggesting glycolysis and oxidative metabolism are inextricably coupled in these cells. The physiological implications of fructose exposure are demonstrated in a model of LPS-induced systemic inflammation, with mice exposed to fructose having increased levels of circulating IL-1β after LPS challenge. Taken together, our work underpins a pro-inflammatory role for dietary fructose in LPS-stimulated mononuclear phagocytes which occurs at the expense of metabolic flexibility.

scholarly journals Experimental Type 2 Diabetes Differently Impacts on the Select Functions of Bone Marrow-Derived Multipotent Stromal Cells

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 268
Author(s):  
Jonathan Ribot ◽  
Cyprien Denoeud ◽  
Guilhem Frescaline ◽  
Rebecca Landon ◽  
Hervé Petite ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Adipogenic Differentiation ◽  
Therapeutic Modality ◽  
Multipotent Stromal Cells ◽  
Cell Therapies

Bone marrow-derived multipotent stromal cells (BMMSCs) represent an attractive therapeutic modality for cell therapy in type 2 diabetes mellitus (T2DM)-associated complications. T2DM changes the bone marrow environment; however, its effects on BMMSC properties remain unclear. The present study aimed at investigating select functions and differentiation of BMMSCs harvested from the T2DM microenvironment as potential candidates for regenerative medicine. BMMSCs were obtained from Zucker diabetic fatty (ZDF; an obese-T2DM model) rats and their lean littermates (ZL; controls), and cultured under normoglycemic conditions. The BMMSCs derived from ZDF animals were fewer in number, with limited clonogenicity (by 2-fold), adhesion (by 2.9-fold), proliferation (by 50%), migration capability (by 25%), and increased apoptosis rate (by 2.5-fold) compared to their ZL counterparts. Compared to the cultured ZL-BMMSCs, the ZDF-BMMSCs exhibited (i) enhanced adipogenic differentiation (increased number of lipid droplets by 2-fold; upregulation of the Pparg, AdipoQ, and Fabp genes), possibly due to having been primed to undergo such differentiation in vivo prior to cell isolation, and (ii) different angiogenesis-related gene expression in vitro and decreased proangiogenic potential after transplantation in nude mice. These results provided evidence that the T2DM environment impairs BMMSC expansion and select functions pertinent to their efficacy when used in autologous cell therapies.

scholarly journals Differential responses of human monocytes and macrophages to IL-4 and IL-13

1999 ◽  
Vol 66 (4) ◽  
pp. 575-578 ◽  
Author(s):  
Prue H. Hart ◽  
Claudine S. Bonder ◽  
Julianna Balogh ◽  
Harold L. Dickensheets ◽  
Raymond P. Donnelly ◽  
...  
Keyword(s):  
Human Monocytes ◽  
Monocytes And Macrophages ◽  
Differential Responses ◽  
Human Monocytes And Macrophages

scholarly journals Lineage−Sca1+c-Kit−CD25+ Cells Are IL-33–Responsive Type 2 Innate Cells in the Mouse Bone Marrow

2011 ◽  
Vol 187 (11) ◽  
pp. 5795-5804 ◽  
Author(s):  
Adipong Brickshawana ◽  
Virginia Smith Shapiro ◽  
Hirohito Kita ◽  
Larry R. Pease
Keyword(s):  
Bone Marrow ◽  
Mouse Bone Marrow

CD4+ T-cell activation of bone marrow causes bone fragility and insulin resistance in type 2 diabetes

Bone ◽  
2021 ◽  
pp. 116292
Author(s):  
S.E. Cifuentes-Mendiola ◽  
D.L. Solis-Suarez ◽  
A. Martínez-Dávalos ◽  
M. Godínez-Victoria ◽  
A.L. García-Hernández
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Bone Marrow ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bone Fragility ◽  
Cd4 T Cell

Evaluation of Congenital Neutropenic Disorders by in Vitro Bone Marrow Culture

PEDIATRICS ◽  
1977 ◽  
Vol 59 (5) ◽  
pp. 739-748
Author(s):  
Peter M. Falk ◽  
Kenneth Rich ◽  
Stephen Feig ◽  
E. Richard Stiehm ◽  
David W. Golde ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Severe Disease ◽  
Stem Cell Differentiation ◽  
Peripheral Blood Cell ◽  
Clinical Expression ◽  
Essentially Normal ◽  
Cell Counts

The congenital neutropenias are a heterogeneous group of diseases whose etiology and pathogenesis are largely unknown. We studied nine neutropenic patients from seven families. Evaluation included peripheral blood cell and differential cell counts, epinephrine and typhoid vaccine stimulation studies, Rebuck skin windows, and bone marrow aspirations for morphological assessment and for in vitro culture in liquid suspension and in agar plates. Parallel cultures were set up with and without colony-stimulating activity (CSA), and peripheral leukocytes were assayed for cellular production of CSA. Patients were initially classified on the basis of their clinical course: benign, mild, moderately severe, or severe disease. One patient in the moderately severe group had an immunoglobulin disorder. Morphologically normal mature granulocytes were seen in bone marrow aspirates of two patients, and maturational defects of varying degree were seen in the remaining seven. Colony formation in agar was markedly reduced below normal in three of seven, moderately reduced in two of seven, and greater than normal in two patients. Colonies in six of seven patients consisted exclusively of macrophages. Marrow from all but one of the nine patients demonstrated poor neutrophil development in suspension culture, and addition of CSA did not result in augmented granulocytic proliferation or maturation. A scheme of normal neutrophil maturation is proposed, and the nine patients were categorized according to this scheme. Four patterns of congenital neutropenia emerged: type 1 was the most benign form of disease with essentially normal clinical and in vitro parameters, and a defect considered to be due to a small committed stem cell pool, abnormal release, or excessive utilization peripherally; type 2 had mild disease with presumed defective committed stem cell differentiation along the granulocyte line; type 3 included benign to severe clinical expression with an apparent defect at the level of the committed granulocyte precursor more severe than in type 2; type 4 disease had varied clinical expression but evidence for a defect at the level of the pluripotent stem cell.

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