scholarly journals A Modified Collagen Dressing Induces Transition of Inflammatory to Reparative Phenotype of Wound Macrophages

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Amitava Das ◽  
Motaz Abas ◽  
Nirupam Biswas ◽  
Pradipta Banerjee ◽  
Nandini Ghosh ◽  
...  
Keyword(s):  
Apoptotic Cell ◽  
Wound Care ◽  
Macrophage Polarization ◽  
Collagen Gel ◽  
Causative Factor ◽  
Macrophage Phenotype ◽  
Direct Role ◽  
Jnk Pathway ◽  
Wound Site ◽  
Anti Inflammatory

Abstract Collagen containing wound-care dressings are extensively used. However, the mechanism of action of these dressings remain unclear. Earlier studies utilizing a modified collagen gel (MCG) dressing demonstrated improved vascularization of ischemic wounds and better healing outcomes. Wound macrophages are pivotal in facilitating wound angiogenesis and timely healing. The current study was designed to investigate the effect of MCG on wound macrophage phenotype and function. MCG augmented recruitment of macrophage at the wound-site, attenuated pro-inflammatory and promoted anti-inflammatory macrophage polarization. Additionally, MCG increased anti-inflammatory IL-10, IL-4 and pro-angiogenic VEGF production, indicating a direct role of MCG in resolving wound inflammation and improving angiogenesis. At the wound-site, impairment in clearance of apoptotic cell bioburden enables chronic inflammation. Engulfment of apoptotic cells by macrophages (efferocytosis) resolves inflammation via a miR-21-PDCD4-IL-10 pathway. MCG-treated wound macrophages exhibited a significantly bolstered efferocytosis index. Such favorable outcome significantly induced miR-21 expression. MCG-mediated IL-10 production was dampened under conditions of miR-21 knockdown pointing towards miR-21 as a causative factor. Pharmacological inhibition of JNK attenuated IL-10 production by MCG, implicating miR-21-JNK pathway in MCG-mediated IL-10 production by macrophages. This work provides direct evidence demonstrating that a collagen-based wound-care dressing may influence wound macrophage function and therefore modify wound inflammation outcomes.

scholarly journals Hyperoxia Exacerbates Postnatal Inflammation-Induced Lung Injury in Neonatal BRP-39 Null Mutant Mice Promoting the M1 Macrophage Phenotype

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Mansoor A. Syed ◽  
Vineet Bhandari
Keyword(s):  
Lung Injury ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Continuous Exposure ◽  
Macrophage Phenotype ◽  
Cell Counts ◽  
M1 Macrophage ◽  
Neonatal Lung ◽  
Neonatal Lung Injury ◽  
Anti Inflammatory

Rationale. Hyperoxia exposure to developing lungs—critical in the pathogenesis of bronchopulmonary dysplasia—may augment lung inflammation by inhibiting anti-inflammatory mediators in alveolar macrophages.Objective. We sought to determine the O2-induced effects on the polarization of macrophages and the role of anti-inflammatory BRP-39 in macrophage phenotype and neonatal lung injury.Methods. We used RAW264.7, peritoneal, and bone marrow derived macrophages for polarization (M1/M2) studies. Forin vivostudies, wild-type (WT) and BRP-39−/−mice received continuous exposure to 21% O2(control mice) or 100% O2from postnatal (PN) 1 to PN7 days, along with intranasal lipopolysaccharide (LPS) administered on alternate days (PN2, -4, and -6). Lung histology, bronchoalveolar lavage (BAL) cell counts, BAL protein, and cytokines measurements were performed.Measurements and Main Results. Hyperoxia differentially contributed to macrophage polarization by enhancing LPS induced M1 and inhibiting interleukin-4 induced M2 phenotype. BRP-39 absence led to further enhancement of the hyperoxia and LPS induced M1 phenotype. In addition, BRP-39−/−mice were significantly more sensitive to LPS plus hyperoxia induced lung injury and mortality compared to WT mice.Conclusions. These findings collectively indicate that BRP-39 is involved in repressing the M1 proinflammatory phenotype in hyperoxia, thereby deactivating inflammatory responses in macrophages and preventing neonatal lung injury.

Supramolecular copolymer modified statins-loaded discoidal rHDLs for atherosclerotic anti-inflammatory therapy by cholesterol efflux and M2 macrophage polarization

2021 ◽  
Author(s):  
Qiqi Zhang ◽  
Jianhua He ◽  
Fengfei Xu ◽  
Xinya Huang ◽  
Yanyan Wang ◽  
...  
Keyword(s):  
Essential Role ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Cholesterol Removal ◽  
Atherosclerosis Progression ◽  
Inflammatory Phenotype ◽  
M2 Macrophage Polarization ◽  
Anti Inflammatory ◽  
Inflammatory Macrophage

Foam cells with the pro-inflammatory macrophage phenotype (M1) play an essential role in atherosclerosis progression. Either cellular cholesterol removal or drug intervention was reported to polarize M1 into anti-inflammatory phenotype...

scholarly journals Effects of Eltrombopag on In Vitro Macrophage Polarization in Pediatric Immune Thrombocytopenia

2020 ◽  
Vol 22 (1) ◽  
pp. 97
Author(s):  
Alessandra Di Paola ◽  
Giuseppe Palumbo ◽  
Pietro Merli ◽  
Maura Argenziano ◽  
Chiara Tortora ◽  
...  
Keyword(s):  
Immune Thrombocytopenia ◽  
Macrophage Polarization ◽  
Macrophage Phenotype ◽  
Activated Macrophages ◽  
T Helper ◽  
T Helper 1 ◽  
Alternatively Activated Macrophages ◽  
Effector Cells ◽  
Anti Inflammatory

Immune Thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibodies-mediated platelet destruction, a prevalence of M1 pro-inflammatory macrophage phenotype and an elevated T helper 1 and T helper 2 lymphocytes (Th1/Th2) ratio, resulting in impairment of inflammatory profile and immune response. Macrophages are immune cells, present as pro-inflammatory classically activated macrophages (M1) or as anti-inflammatory alternatively activated macrophages (M2). They have a key role in ITP, acting both as effector cells, phagocytizing platelets, and, as antigen presenting cells, stimulating auto-antibodies against platelets production. Eltrombopag (ELT) is a thrombopoietin receptor agonist licensed for chronic ITP to stimulate platelet production. Moreover, it improves T and B regulatory cells functions, suppresses T-cells activity, and inhibits monocytes activation. We analyzed the effect of ELT on macrophage phenotype polarization, proposing a new possible mechanism of action. We suggest it as a mediator of macrophage phenotype switch from the M1 pro-inflammatory type to the M2 anti-inflammatory one in paediatric patients with ITP, in order to reduce inflammatory state and restore the immune system function. Our results provide new insights into the therapy and the management of ITP, suggesting ELT also as immune-modulating drug.

scholarly journals Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages

2017 ◽  
Vol 474 (4) ◽  
pp. 521-537 ◽  
Author(s):  
Nicola J. Darling ◽  
Rachel Toth ◽  
J. Simon C. Arthur ◽  
Kristopher Clark
Keyword(s):  
Inflammatory Cytokines ◽  
Drug Targets ◽  
Macrophage Polarization ◽  
Macrophage Phenotype ◽  
Integral Role ◽  
Inflammatory Phenotype ◽  
Low Levels ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Pro Inflammatory Cytokines

The salt-inducible kinases (SIKs) control a novel molecular switch regulating macrophage polarization. Pharmacological inhibition of the SIKs induces a macrophage phenotype characterized by the secretion of high levels of anti-inflammatory cytokines, including interleukin (IL)-10, and the secretion of very low levels of pro-inflammatory cytokines, such as tumour necrosis factor α. The SIKs, therefore, represent attractive new drug targets for the treatment of macrophage-driven diseases, but which of the three isoforms, SIK1, SIK2 or SIK3, would be appropriate to target remains unknown. To address this question, we developed knock-in (KI) mice for SIK1, SIK2 and SIK3, in which we introduced a mutation that renders the enzymes catalytically inactive. Characterization of primary macrophages from the single and double KI mice established that all three SIK isoforms, and in particular SIK2 and SIK3, contribute to macrophage polarization. Moreover, we discovered that inhibition of SIK2 and SIK3 during macrophage differentiation greatly enhanced the production of IL-10 compared with their inhibition in mature macrophages. Interestingly, macrophages differentiated in the presence of SIK inhibitors, MRT199665 and HG-9-91-01, still produced very large amounts of IL-10, but very low levels of pro-inflammatory cytokines, even after the SIKs had been reactivated by removal of the drugs. Our data highlight an integral role for SIK2 and SIK3 in innate immunity by preventing the differentiation of macrophages into a potent and stable anti-inflammatory phenotype.

Abstract 17035: Inhibition of DNMT and HDAC6 Together Regulates Macrophage Polarization by FoxO1-HIF2α Signaling and Protects Endotoxemia-Induced Inflammation

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Saheli Samanta ◽  
Zhigang Zhou ◽  
Sheeja Rajasingh ◽  
Kyley K Burkey ◽  
Rajasingh Johnson
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Combined Treatment ◽  
Cell Polarization ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Therapeutic Drugs ◽  
Protein Expressions ◽  
Anti Inflammatory

Introduction: Acute lung injury (ALI) is a common pulmonary disease caused by bacterial infection leading to an imbalance between pro-inflammatory and anti-inflammatory immune responses. Studies have shown that macrophage polarization (M1 and M2) during ALI plays a key role in regulating these responses. Hypothesis: We hypothesized that combined treatment with 5-Aza 2-deoxycytidine (Aza) + tubastatin A (TBA) would reduce inflammation and promote an anti-inflammatory M2 macrophage phenotype by regulating the HIF2α signaling pathway. Methods: To show the effect of Aza+TBA, lipopolysaccharide (LPS)-induced macrophages (RAW 264.7) were treated with either Aza (50nM), TBA n(750nM), or together (Aza+TBA) for 24 hours. The mRNA and protein expressions of FoxO1, HIF2α, NOS2 (M1), and CD206 (M2) were measured by qRT-PCR and Western analyses in lung tissue and macrophages. Results: Our results revealed that LPS induced macrophages showed an increased expression of NOS2 (M1) and decreased expression of Fizz-1 (M2) whereas the LPS-induced macrophages were treated with Aza+TBA showed decreased NOS2 (Fig. A) and increased Fizz-1 mRNA (Fig. B) and protein expressions. Furthermore, the LPS significantly decreased the mRNA and protein expressions of FoxO1 and HIF2α in macrophages. These expressions were significantly increased when the LPS-induced macrophages were treated with Aza +TBA (Fig. C) . These results suggest that Aza+TBA treatment together generates more M2 macrophages there by reducing the LPS-induced inflammatory responses. Conclusions: Overall, these data show the first time that the combinatorial treatment with Aza+TBA regulates macrophage cell polarization and abrogates LPS-induced inflammation through FoxO1-HIF2α signaling pathway. Thus, epigenetic modifiers may be potential therapeutic drugs for ALI. <!--EndFragment-->

Mechanobiology of Macrophages: How Physical Factors Coregulate Macrophage Plasticity and Phagocytosis

2019 ◽  
Vol 21 (1) ◽  
pp. 267-297 ◽  
Author(s):  
Nikhil Jain ◽  
Jens Moeller ◽  
Viola Vogel
Keyword(s):  
Inflammatory Diseases ◽  
Apoptotic Cell ◽  
Macrophage Polarization ◽  
New Drugs ◽  
Physical Factors ◽  
Macrophage Phenotype ◽  
Pathological Conditions ◽  
Macrophage Plasticity ◽  
And Function ◽  
Made In

In addition to their early-recognized functions in host defense and the clearance of apoptotic cell debris, macrophages play vital roles in tissue development, homeostasis, and repair. If misregulated, they steer the progression of many inflammatory diseases. Much progress has been made in understanding the mechanisms underlying macrophage signaling, transcriptomics, and proteomics, under physiological and pathological conditions. Yet, the detailed mechanisms that tune circulating monocytes/macrophages and tissue-resident macrophage polarization, differentiation, specification, and their functional plasticity remain elusive. We review how physical factors affect macrophage phenotype and function, including how they hunt for particles and pathogens, as well as the implications for phagocytosis, autophagy, and polarization from proinflammatory to prohealing phenotype. We further discuss how this knowledge can be harnessed in regenerative medicine and for the design of new drugs and immune-modulatory drug delivery systems, biomaterials, and tissue scaffolds.

scholarly journals The crosstalk of ABCA1 and ANXA1: a potential mechanism for protection against atherosclerosis

2020 ◽  
Vol 26 (1) ◽  
Author(s):  
Xin Shen ◽  
Shun Zhang ◽  
Zhu Guo ◽  
Dongming Xing ◽  
Wujun Chen
Keyword(s):  
Cell Membrane ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Serine Phosphorylation ◽  
Basic Knowledge ◽  
Dependent Manner ◽  
Direct Role ◽  
Abca1 Expression ◽  
Anti Inflammatory

Abstract Atherosclerosis, characterized by the formation of fat-laden plaques, is a chronic inflammatory disease. ABCA1 promotes cholesterol efflux, reduces cellular cholesterol accumulation, and regulates anti-inflammatory activities in an apoA-I- or ANXA1-dependent manner. The latter activity occurs by mediating the efflux of ANXA1, which plays a critical role in anti-inflammatory effects, cholesterol transport, exosome and microparticle secretion, and apoptotic cell clearance. ApoA-I increases ANXA1 expression via the ERK, p38MAPK, AKT, and PKC pathways. ApoA-I regulates the signaling pathways by binding to ABCA1, suggesting that apoA-I increases ANXA1 expression by binding to ABCA1. Furthermore, ANXA1 may increase ABCA1 expression. ANXA1 increases PPARγ expression by modulating STAT6 phosphorylation. PPARγ also increases ANXA1 expression by binding to the promoter of ANXA1. Therefore, ABCA1, PPARγ, and ANXA1 may form a feedback loop and regulate each other. Interestingly, the ANXA1 needs to be externalized to the cell membrane or secreted into the extracellular fluids to exert its anti-inflammatory properties. ABCA1 transports ANXA1 from the cytoplasm to the cell membrane by regulating lipidization and serine phosphorylation, thereby mediating ANXA1 efflux, likely by promoting microparticle and exosome release. The direct role of ABCA1 expression and ANXA1 release in atherosclerosis has been unclear. In this review, we focus on the role of ANXA1 in atheroprogression and its novel interaction with ABCA1, which may be useful for providing basic knowledge for the development of novel therapeutic targets for atherosclerosis and cardiovascular disease.

scholarly journals Statins Directly Influence the Polarization of Adipose Tissue Macrophages: A Role in Chronic Inflammation

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 211
Author(s):  
Sona Kauerova ◽  
Hana Bartuskova ◽  
Barbora Muffova ◽  
Libor Janousek ◽  
Jiri Fronek ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Ldl Cholesterol ◽  
Macrophage Polarization ◽  
Inflammatory Activity ◽  
Human Macrophage ◽  
Macrophage Phenotype ◽  
Anti Inflammatory ◽  
Inflammatory Macrophages ◽  
Inflammatory Macrophage

Statins represent one of the most widely used classes of drugs in current medicine. In addition to a substantial decrease in atherogenic low density lipoprotein (LDL) particle concentrations, several large trials have documented their potent anti-inflammatory activity. Based on our preliminary data, we showed that statins are able to decrease the proportion of pro-inflammatory macrophages (CD14+16+CD36high) in visceral adipose tissue in humans. In the present study including 118 healthy individuals (living kidney donors), a very close relationship between the pro-inflammatory macrophage proportion and LDL cholesterol levels was found. This was confirmed after adjustment for the most important risk factors. The effect of statins on the proportion of pro-inflammatory macrophages was also confirmed in an experimental model of the Prague hereditary hypercholesterolemia rat. A direct anti-inflammatory effect of fluvastatin on human macrophage polarization in vitro was documented. Based on modifying the LDL cholesterol concentrations, statins are suggested to decrease the cholesterol inflow through the lipid raft of macrophages in adipose tissue and hypercholesterolemia to enhance the pro-inflammatory macrophage phenotype polarization. On the contrary, due to their opposite effect, statins respond with anti-inflammatory activity, affecting the whole organism.

scholarly journals Impaired apoptotic cell clearance in CGD due to altered macrophage programming is reversed by phosphatidylserine-dependent production of IL-4

Blood ◽  
2009 ◽  
Vol 113 (9) ◽  
pp. 2047-2055 ◽  
Author(s):  
Ruby F. Fernandez-Boyanapalli ◽  
S. Courtney Frasch ◽  
Kathleen McPhillips ◽  
R. William Vandivier ◽  
Brian L. Harry ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Apoptotic Cell ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Alternative Activation ◽  
Peroxisome Proliferator ◽  
Macrophage Phenotype ◽  
Peroxisome Proliferator Activated Receptor ◽  
Anti Inflammatory

Chronic granulomatous disease (CGD) is characterized by overexuberant inflammation and autoimmunity that are attributed to deficient anti-inflammatory signaling. Although regulation of these processes is complex, phosphatidylserine (PS)–dependent recognition and removal of apoptotic cells (efferocytosis) by phagocytes are potently anti-inflammatory. Since macrophage phenotype also plays a beneficial role in resolution of inflammation, we hypothesized that impaired efferocytosis in CGD due to macrophage skewing contributes to enhanced inflammation. Here we demonstrate that efferocytosis by macrophages from CGD (gp91phox−/−) mice was suppressed ex vivo and in vivo. Alternative activation with interleukin 4 (IL-4) normalized CGD macrophage efferocytosis, whereas classical activation by lipopolysaccharide (LPS) plus interferon γ (IFNγ) had no effect. Importantly, neutralization of IL-4 in wild-type macrophages reduced macrophage efferocytosis, demonstrating a central role for IL-4. This effect was shown to involve 12/15 lipoxygenase and activation of peroxisome-proliferator activated receptor γ (PPARγ). Finally, injection of PS (whose exposure is lacking on CGD apoptotic neutrophils) in vivo restored IL-4–dependent macrophage reprogramming and efferocytosis via a similar mechanism. Taken together, these findings support the hypothesis that impaired PS exposure on dying cells results in defective macrophage programming, with consequent efferocytic impairment and has important implications in understanding the underlying cause of enhanced inflammation in CGD.

scholarly journals Macrophages: The Good, the Bad, and the Gluttony

2021 ◽  
Vol 12 ◽  
Author(s):  
Ewan A. Ross ◽  
Andrew Devitt ◽  
Jill R. Johnson
Keyword(s):  
Allergic Asthma ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Apoptotic Cell ◽  
Macrophage Polarization ◽  
Lymphoid Cells ◽  
Sterile Inflammation ◽  
Phenotypic Switching ◽  
Macrophage Phenotype ◽  
The Impact

Macrophages are dynamic cells that play critical roles in the induction and resolution of sterile inflammation. In this review, we will compile and interpret recent findings on the plasticity of macrophages and how these cells contribute to the development of non-infectious inflammatory diseases, with a particular focus on allergic and autoimmune disorders. The critical roles of macrophages in the resolution of inflammation will then be examined, emphasizing the ability of macrophages to clear apoptotic immune cells. Rheumatoid arthritis (RA) is a chronic autoimmune-driven spectrum of diseases where persistent inflammation results in synovial hyperplasia and excessive immune cell accumulation, leading to remodeling and reduced function in affected joints. Macrophages are central to the pathophysiology of RA, driving episodic cycles of chronic inflammation and tissue destruction. RA patients have increased numbers of active M1 polarized pro-inflammatory macrophages and few or inactive M2 type cells. This imbalance in macrophage homeostasis is a main contributor to pro-inflammatory mediators in RA, resulting in continual activation of immune and stromal populations and accelerated tissue remodeling. Modulation of macrophage phenotype and function remains a key therapeutic goal for the treatment of this disease. Intriguingly, therapeutic intervention with glucocorticoids or other DMARDs promotes the re-polarization of M1 macrophages to an anti-inflammatory M2 phenotype; this reprogramming is dependent on metabolic changes to promote phenotypic switching. Allergic asthma is associated with Th2-polarised airway inflammation, structural remodeling of the large airways, and airway hyperresponsiveness. Macrophage polarization has a profound impact on asthma pathogenesis, as the response to allergen exposure is regulated by an intricate interplay between local immune factors including cytokines, chemokines and danger signals from neighboring cells. In the Th2-polarized environment characteristic of allergic asthma, high levels of IL-4 produced by locally infiltrating innate lymphoid cells and helper T cells promote the acquisition of an alternatively activated M2a phenotype in macrophages, with myriad effects on the local immune response and airway structure. Targeting regulators of macrophage plasticity is currently being pursued in the treatment of allergic asthma and other allergic diseases. Macrophages promote the re-balancing of pro-inflammatory responses towards pro-resolution responses and are thus central to the success of an inflammatory response. It has long been established that apoptosis supports monocyte and macrophage recruitment to sites of inflammation, facilitating subsequent corpse clearance. This drives resolution responses and mediates a phenotypic switch in the polarity of macrophages. However, the role of apoptotic cell-derived extracellular vesicles (ACdEV) in the recruitment and control of macrophage phenotype has received remarkably little attention. ACdEV are powerful mediators of intercellular communication, carrying a wealth of lipid and protein mediators that may modulate macrophage phenotype, including a cargo of active immune-modulating enzymes. The impact of such interactions may result in repair or disease in different contexts. In this review, we will discuss the origin, characterization, and activity of macrophages in sterile inflammatory diseases and the underlying mechanisms of macrophage polarization via ACdEV and apoptotic cell clearance, in order to provide new insights into therapeutic strategies that could exploit the capabilities of these agile and responsive cells.

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