scholarly journals Non-Genetic Reprogramming of Monocytes via Microparticle Phagocytosis for Sustained Modulation of Macrophage Phenotype

2019 ◽  
Author(s):  
Kathryn L. Wofford ◽  
Bhavani S. Singh ◽  
D. Kacy Cullen ◽  
Kara L. Spiller
Keyword(s):  
Cell Therapy ◽  
Inflammatory Factors ◽  
Macrophage Phenotype ◽  
Vast Number ◽  
Inflammatory Drug ◽  
Rapid Acquisition ◽  
Therapy Strategy ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory ◽  
Over Time

ABSTRACTMonocyte-derived macrophages orchestrate tissue regeneration by homing to sites of injury, phagocytosing pathological debris, and stimulating other cell types to repair the tissue. Accordingly, monocytes have been investigated as a translational and potent source for cell therapy, but their utility has been hampered by their rapid acquisition of a pro-inflammatory phenotype in response to the inflammatory injury microenvironment. To overcome this problem, we designed a cell therapy strategy where we collect and exogenously reprogram monocytes by intracellularly loading the cells with biodegradable microparticles containing an anti-inflammatory drug in order to modulate and maintain an anti-inflammatory phenotype over time. To test this concept, poly(lactic-co-glycolic) acid microparticles were loaded with the anti-inflammatory drug dexamethasone (Dex) and administered to primary human monocytes for four hours to facilitate phagocytic uptake. After removal of non-phagocytosed microparticles, microparticle-loaded monocytes differentiated into macrophages and stored the microparticles intracellularly for several weeks in vitro, releasing drug into the extracellular environment over time. Cells loaded with intracellular Dex microparticles showed decreased expression and secretion of inflammatory factors even in the presence of pro-inflammatory stimuli up to 7 days after microparticle uptake compared to untreated cells or cells loaded with blank microparticles. This study represents a new strategy for long-term maintenance of anti-inflammatory macrophage phenotype using a translational monocyte-based cell therapy strategy without the use of genetic modification. Because of the ubiquitous nature of monocyte-derived macrophage involvement in pathology and regeneration, this strategy holds potential as a treatment for a vast number of diseases and disorders.

scholarly journals Longitudinal transcriptomics define the stages of myeloid activation in the living human brain after intracerebral hemorrhage

2021 ◽  
Vol 6 (56) ◽  
pp. eabd6279
Author(s):  
Michael H. Askenase ◽  
Brittany A. Goods ◽  
Hannah E. Beatty ◽  
Arthur F. Steinschneider ◽  
Sofia E. Velazquez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Injury ◽  
Immune Responses ◽  
Intracerebral Hemorrhage ◽  
Human Brain ◽  
Inflammatory Factors ◽  
Lipid Mediator ◽  
Prostaglandin E ◽  
Anti Inflammatory ◽  
Over Time

Opportunities to interrogate the immune responses in the injured tissue of living patients suffering from acute sterile injuries such as stroke and heart attack are limited. We leveraged a clinical trial of minimally invasive neurosurgery for patients with intracerebral hemorrhage (ICH), a severely disabling subtype of stroke, to investigate the dynamics of inflammation at the site of brain injury over time. Longitudinal transcriptional profiling of CD14+ monocytes/macrophages and neutrophils from hematomas of patients with ICH revealed that the myeloid response to ICH within the hematoma is distinct from that in the blood and occurs in stages conserved across the patient cohort. Initially, hematoma myeloid cells expressed a robust anabolic proinflammatory profile characterized by activation of hypoxia-inducible factors (HIFs) and expression of genes encoding immune factors and glycolysis. Subsequently, inflammatory gene expression decreased over time, whereas anti-inflammatory circuits were maintained and phagocytic and antioxidative pathways up-regulated. During this transition to immune resolution, glycolysis gene expression and levels of the potent proresolution lipid mediator prostaglandin E2 remained elevated in the hematoma, and unexpectedly, these elevations correlated with positive patient outcomes. Ex vivo activation of human macrophages by ICH-associated stimuli highlighted an important role for HIFs in production of both inflammatory and anti-inflammatory factors, including PGE2, which, in turn, augmented VEGF production. Our findings define the time course of myeloid activation in the human brain after ICH, revealing a conserved progression of immune responses from proinflammatory to proresolution states in humans after brain injury and identifying transcriptional programs associated with neurological recovery.

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 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.

scholarly journals Gastroprotective Agent Underuse in High-Risk Older Daily Nonsteroidal Anti-Inflammatory Drug Users over Time

2014 ◽  
Vol 62 (10) ◽  
pp. 1923-1927 ◽  
Author(s):  
Zachary A. Marcum ◽  
Joseph T. Hanlon ◽  
Elsa S. Strotmeyer ◽  
Anne B. Newman ◽  
Ronald I. Shorr ◽  
...  
Keyword(s):  
High Risk ◽  
Drug Users ◽  
Inflammatory Drug ◽  
Gastroprotective Agent ◽  
Anti Inflammatory ◽  
Over Time

scholarly journals Effects of ibuprofen on gene expression in chondrocytes from patients with osteoarthritis as determined by RNA-Seq

RMD Open ◽  
2021 ◽  
Vol 7 (3) ◽  
pp. e001657
Author(s):  
Antti Pemmari ◽  
Lauri Tuure ◽  
Mari Hämäläinen ◽  
Tiina Leppänen ◽  
Teemu Moilanen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Symptomatic Treatment ◽  
Inflammatory Factors ◽  
Rna Seq ◽  
Replacement Surgery ◽  
Inflammatory Conditions ◽  
Mediators Of Inflammation ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory ◽  
Upregulated Genes

Non-steroidal anti-inflammatory drugs are a widely used symptomatic treatment in osteoarthritis (OA), but their effects on cartilage remain controversial. We studied the effects of ibuprofen on gene expression in chondrocytes from patients with OA using RNA-Seq. Chondrocytes were isolated from cartilage samples of patients with OA undergoing knee replacement surgery, cultured with ibuprofen, and total mRNA was sequenced. Differentially expressed genes were identified with edgeR using pairwise comparisons. Functional analysis was performed using ingenuity pathway analysis (IPA). Ibuprofen did not induce statistically significant changes in chondrocyte transcriptome when the cells were cultured in the absence of added cytokines. In inflammatory conditions (when the cells were exposed to the OA-related cytokine interleukin (IL)-1β), 51 genes were upregulated and 42 downregulated by ibuprofen with fold change >1.5 in either direction. The upregulated genes included anti-inflammatory factors and genes associated with cell adhesion, while several mediators of inflammation were among the downregulated genes. IPA analysis revealed ibuprofen having modulating effects on inflammation-related pathways such as integrin, IL-8, ERK/MAPK and cAMP-mediated signalling pathways. In conclusion, the effects of ibuprofen on primary OA chondrocyte transcriptome appear to be neutral in normal conditions, but ibuprofen may shift chondrocyte transcriptome towards anti-inflammatory phenotype in inflammatory environments.

scholarly journals MicroRNA-223-3p promotes skeletal muscle regeneration by regulating inflammation in mice

2020 ◽  
Vol 295 (30) ◽  
pp. 10212-10223 ◽  
Author(s):  
Naixuan Cheng ◽  
Chang Liu ◽  
Yulin Li ◽  
Shijuan Gao ◽  
Ying-Chun Han ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Molecular Mechanisms ◽  
Interstitial Fibrosis ◽  
Early Stage ◽  
Skeletal Muscle Regeneration ◽  
Inflammatory Factors ◽  
Regeneration Ability ◽  
Macrophage Phenotype ◽  
Anti Inflammatory

After injury, the coordinated balance of pro- and anti-inflammatory factors in the microenvironment contribute to skeletal muscle regeneration. However, the underlying molecular mechanisms regulating this balance remain incompletely understood. In this study, we examined the roles of microRNAs (miRNAs) in inflammation and muscle regeneration. miRNA-Seq transcriptome analysis of mouse skeletal muscle revealed that miR-223-3p is upregulated in the early stage of muscle regeneration after injury. miR-223-3p knockout resulted in increased inflammation, impaired muscle regeneration, and increased interstitial fibrosis. Mechanistically, we found that myeloid-derived miR-223-3p suppresses the target gene interleukin-6 (Il6), associated with the maintenance of the proinflammatory macrophage phenotype during injury. Administration of IL-6-neutralizing antibody in miR-223-3p-knockout muscle could rescue the impaired regeneration ability and reduce the fibrosis. Together, our results reveal that miR-223-3p improves muscle regeneration by regulating inflammation, indicating that miRNAs can participate in skeletal muscle regeneration by controlling the balance of pro- and anti-inflammatory factors in the skeletal muscle microenvironment.

scholarly journals M1 macrophages are required for murine cerebral aneurysm formation

2017 ◽  
Vol 10 (1) ◽  
pp. 93-97 ◽  
Author(s):  
Kamil W Nowicki ◽  
Koji Hosaka ◽  
Frank J Walch ◽  
Edward W Scott ◽  
Brian L Hoh
Keyword(s):  
Cerebral Aneurysm ◽  
Macrophage Polarization ◽  
Cerebral Aneurysms ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Aneurysm Formation ◽  
Inflammatory Phenotype ◽  
M1 Phenotype ◽  
Aneurysm Development ◽  
Over Time

IntroductionMacrophages and neutrophils have been separately implicated in cerebral aneurysm formation. The interactions between different myeloid subsets and the contributions of macrophage phenotypes in these lesions over time are not known. The purpose of the study was to examine macrophage phenotypic changes in cerebral aneurysms.MethodsWe induced aneurysm formation in C57BL/6 mice and quantified contributions of M1 and M2 macrophages in aneurysm specimens with or without neutrophil blockade. In our aneurysm model, the left common carotid and right renal arteries were ligated, and mice were placed on a hypertensive high fat diet. One week later, stereotactic injection with elastase solution into the basal cisterns was performed. An angiotensin II secreting osmotic pump was implanted. The mice were then treated with anti-CXCL1 antibody or IgG control antibody. Animals were euthanized at 3 days, or 1 or 2 weeks. The circle of Willis was analyzed using immunohistochemistry for M1 and M2 macrophage phenotype contributions.ResultsProinflammatory M1/M2 ratio increased in cerebral aneurysm formation over time, from 0.56 at 3 days to 1.75 at 2 weeks (p<0.0001). In contrast, anti-CXCL1 antibody blockade led to polarization towards an anti-inflammatory phenotype with an M1/M2 ratio of 0.95 at 2 weeks compared with IgG treated mice (p=0.0007).ConclusionsCXCL1 dependent neutrophil inflammation appears to have an important role in macrophage polarization to M1 phenotype in cerebral aneurysm development.

A Degenerative/Proinflammatory Intervertebral Disc Organ Culture: An Ex Vivo Model for Anti-inflammatory Drug and Cell Therapy

2016 ◽  
Vol 22 (1) ◽  
pp. 8-19 ◽  
Author(s):  
Graciosa Q. Teixeira ◽  
Antje Boldt ◽  
Ines Nagl ◽  
Catarina Leite Pereira ◽  
Karin Benz ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Intervertebral Disc ◽  
Organ Culture ◽  
Ex Vivo ◽  
Ex Vivo Model ◽  
Inflammatory Drug ◽  
Anti Inflammatory

scholarly journals Brain Tissue-Derived Extracellular Vesicle Mediated Therapy in the Neonatal Ischemic Brain

2022 ◽  
Vol 23 (2) ◽  
pp. 620
Author(s):  
Nam Phuong Nguyen ◽  
Hawley Helmbrecht ◽  
Ziming Ye ◽  
Tolulope Adebayo ◽  
Najma Hashi ◽  
...  
Keyword(s):  
Time Window ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Brain Slices ◽  
Neurological Injury ◽  
Inflammatory Factors ◽  
Dependent Manner ◽  
Therapeutic Dosage ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory

Hypoxic-Ischemic Encephalopathy (HIE) in the brain is the leading cause of morbidity and mortality in neonates and can lead to irreparable tissue damage and cognition. Thus, investigating key mediators of the HI response to identify points of therapeutic intervention has significant clinical potential. Brain repair after HI requires highly coordinated injury responses mediated by cell-derived extracellular vesicles (EVs). Studies show that stem cell-derived EVs attenuate the injury response in ischemic models by releasing neuroprotective, neurogenic, and anti-inflammatory factors. In contrast to 2D cell cultures, we successfully isolated and characterized EVs from whole brain rat tissue (BEV) to study the therapeutic potential of endogenous EVs. We showed that BEVs decrease cytotoxicity in an ex vivo oxygen glucose deprivation (OGD) brain slice model of HI in a dose- and time-dependent manner. The minimum therapeutic dosage was determined to be 25 μg BEVs with a therapeutic application time window of 4–24 h post-injury. At this therapeutic dosage, BEV treatment increased anti-inflammatory cytokine expression. The morphology of microglia was also observed to shift from an amoeboid, inflammatory phenotype to a restorative, anti-inflammatory phenotype between 24–48 h of BEV exposure after OGD injury, indicating a shift in phenotype following BEV treatment. These results demonstrate the use of OWH brain slices to facilitate understanding of BEV activity and therapeutic potential in complex brain pathologies for treating neurological injury in neonates.

scholarly journals Sex-Specific Differences of the Inflammatory State in Experimental Autoimmune Myocarditis

2021 ◽  
Vol 12 ◽  
Author(s):  
Maria Luisa Barcena ◽  
Sarah Jeuthe ◽  
Maximilian H. Niehues ◽  
Sofya Pozdniakova ◽  
Natalie Haritonow ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Female Rats ◽  
Male Rats ◽  
Inflammatory Factors ◽  
Autoimmune Myocarditis ◽  
Male And Female Rats ◽  
Inflammatory Phenotype ◽  
Experimental Autoimmune Myocarditis ◽  
Anti Inflammatory ◽  
Experimental Autoimmune

Increasing evidence suggests male sex as a potential risk factor for a higher incidence of cardiac fibrosis, stronger cardiac inflammation, and dilated cardiomyopathy (DCM) in human myocarditis. Chronic activation of the immune response in myocarditis may trigger autoimmunity. The experimental autoimmune myocarditis (EAM) model has been well established for the study of autoimmune myocarditis, however the role of sex in this pathology has not been fully explored. In this study, we investigated sex differences in the inflammatory response in the EAM model. We analyzed the cardiac function, as well as the inflammatory stage and fibrosis formation in the heart of EAM male and female rats. 21 days after induction of EAM, male EAM rats showed a decreased ejection fraction, stroke volume and cardiac output, while females did not. A significantly elevated number of infiltrates was detected in myocardium in both sexes, indicating the activation of macrophages following EAM induction. The level of anti-inflammatory macrophages (CD68+ ArgI+) was only significantly increased in female hearts. The expression of Col3A1 and fibrosis formation were more prominent in males. Furthermore, prominent pro-inflammatory factors were increased only in male rats. These findings indicate sex-specific alterations in the inflammatory stage of EAM, with a pro-inflammatory phenotype appearing in males and an anti-inflammatory phenotype in females, which both significantly affect cardiac function in autoimmune myocarditis.

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