Glycolytic inhibitor 2-deoxyglucose suppresses inflammatory response in innate immune cells and experimental staphylococcal endophthalmitis

Monocytes and macrophages play a critical role in tissue development, homeostasis, and injury repair. These innate immune cells participate in guiding vascular remodeling, stimulation of local stem and progenitor cells, and structural repair of tissues such as muscle and bone. Therefore, there is a great interest in harnessing this powerful endogenous cell source for therapeutic regeneration through immunoregenerative biomaterial engineering. These materials seek to harness specific subpopulations of monocytes/macrophages to promote repair by influencing their recruitment, positioning, differentiation, and function within a damaged tissue. Monocyte and macrophage phenotypes span a continuum of inflammatory (M1) to anti-inflammatory or pro-regenerative cells (M2), and their heterogeneous functions are highly dependent on microenvironmental cues within the injury niche. Increasing evidence suggests that division of labor among subpopulations of monocytes and macrophages could allow for harnessing regenerative functions over inflammatory functions of myeloid cells; however, the complex balance between necessary functions of inflammatory versus regenerative myeloid cells remains to be fully elucidated. Historically, biomaterial-based therapies for promoting tissue regeneration were designed to minimize the host inflammatory response; although, recent appreciation for the roles that innate immune cells play in tissue repair and material integration has shifted this paradigm. A number of opportunities exist to exploit known signaling systems of specific populations of monocytes/macrophages to promote repair and to better understand the biological and pathological roles of myeloid cells. This review seeks to outline the characteristics of distinct populations of monocytes and macrophages, identify the role of these cells within diverse tissue injury niches, and offer design criteria for immunoregenerative biomaterials given the intrinsic inflammatory response to their implantation.

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Unmetabolized quetiapine exerts an in vitro effect on innate immune cells by modulating inflammatory response and neutrophil extracellular trap formation

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2020.110497 ◽

2020 ◽

Vol 131 ◽

pp. 110497

Author(s):

Bárbara Osmarin Turra ◽

Fernanda Barbisan ◽

Verônica Farina Azzolin ◽

Cibele Ferreira Teixeira ◽

Thamara Flores ◽

...

Keyword(s):

Inflammatory Response ◽

Immune Cells ◽

Innate Immune ◽

Neutrophil Extracellular Trap ◽

Innate Immune Cells ◽

Trap Formation ◽

Extracellular Trap ◽

Vitro Effect

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YAP-mediated mechanotransduction tunes the macrophage inflammatory response

Science Advances ◽

10.1126/sciadv.abb8471 ◽

2020 ◽

Vol 6 (49) ◽

pp. eabb8471

Author(s):

Vijaykumar S. Meli ◽

Hamza Atcha ◽

Praveen Krishna Veerasubramanian ◽

Raji R. Nagalla ◽

Thuy U. Luu ◽

...

Keyword(s):

Inflammatory Response ◽

Immune Cells ◽

Soft Materials ◽

Innate Immune ◽

Substrate Stiffness ◽

Innate Immune Cells ◽

Transcriptional Coactivator ◽

Matrix Properties ◽

Health And Disease

Macrophages are innate immune cells that adhere to the extracellular matrix within tissues. However, how matrix properties regulate their function remains poorly understood. Here, we report that the adhesive microenvironment tunes the macrophage inflammatory response through the transcriptional coactivator YAP. We find that adhesion to soft hydrogels reduces inflammation when compared to adhesion on stiff materials and is associated with reduced YAP expression and nuclear localization. Substrate stiffness and cytoskeletal polymerization, but not adhesive confinement nor contractility, regulate YAP localization. Furthermore, depletion of YAP inhibits macrophage inflammation, whereas overexpression of active YAP increases inflammation. Last, we show in vivo that soft materials reduce expression of inflammatory markers and YAP in surrounding macrophages when compared to stiff materials. Together, our studies identify YAP as a key molecule for controlling inflammation and sensing stiffness in macrophages and may have broad implications in the regulation of macrophages in health and disease.

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Fra-2 Expression in Osteoblasts Regulates Systemic Inflammation and Lung Injury through Osteopontin

Molecular and Cellular Biology ◽

10.1128/mcb.00022-18 ◽

2018 ◽

Vol 38 (22) ◽

Cited By ~ 4

Author(s):

Yubin Luo ◽

Bettina Grötsch ◽

Nicole Hannemann ◽

Maria Jimenez ◽

Natacha Ipseiz ◽

...

Keyword(s):

Bone Marrow ◽

Lung Injury ◽

Inflammatory Response ◽

Immune Cells ◽

Inflammatory Responses ◽

Bone Marrow Microenvironment ◽

Innate Immune ◽

Bone Marrow Niche ◽

Innate Immune Cells ◽

Molecular Changes

ABSTRACT Inflammatory responses require mobilization of innate immune cells from the bone marrow. The functionality of this process depends on the state of the bone marrow microenvironment. We therefore hypothesized that molecular changes in osteoblasts, which are essential stromal cells of the bone marrow microenvironment, influence the inflammatory response. Here, we show that osteoblast-specific expression of the AP-1 transcription factor Fra-2 (Fra-2Ob-tet) induced a systemic inflammatory state with infiltration of neutrophils and proinflammatory macrophages into the spleen and liver as well as increased levels of proinflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). By in vivo inhibition of osteopontin (OPN) in Fra-2Ob-tet mice, we demonstrated that this process was dependent on OPN expression, which mediates alterations of the bone marrow niche. OPN expression was transcriptionally enhanced by Fra-2 and stimulated mesenchymal stem cell (MSC) expansion. Furthermore, in a murine lung injury model, Fra-2Ob-tet mice showed increased inflammatory responses and more severe disease features via an enhanced and sustained inflammatory response to lipopolysaccharide (LPS). Our findings demonstrate for the first time that molecular changes in osteoblasts influence the susceptibility to inflammation by altering evasion of innate immune cells from the bone marrow space.

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