scholarly journals Pinosylvin Shifts Macrophage Polarization to Support Resolution of Inflammation

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2772
Author(s):  
Konsta Kivimäki ◽  
Tiina Leppänen ◽  
Mari Hämäläinen ◽  
Katriina Vuolteenaho ◽  
Eeva Moilanen
Keyword(s):  
Macrophage Activation ◽  
Environmental Changes ◽  
Macrophage Polarization ◽  
Resolution Of Inflammation ◽  
Human Macrophages ◽  
Arginase 1 ◽  
M1 Phenotype ◽  
Anti Inflammatory ◽  
M1 Type ◽  
M2 Phenotype

Pinosylvin is a natural stilbenoid found particularly in Scots pine. Stilbenoids are a group of phenolic compounds identified as protective agents against pathogens for many plants. Stilbenoids also possess health-promoting properties in humans; for instance, they are anti-inflammatory through their suppressing action on proinflammatory M1-type macrophage activation. Macrophages respond to environmental changes by polarizing towards proinflammatory M1 phenotype in infection and inflammatory diseases, or towards anti-inflammatory M2 phenotype, mediating resolution of inflammation and repair. In the present study, we investigated the effects of pinosylvin on M2-type macrophage activation, aiming to test the hypothesis that pinosylvin could polarize macrophages from M1 to M2 phenotype to support resolution of inflammation. We used lipopolysaccharide (LPS) to induce M1 phenotype and interleukin-4 (IL-4) to induce M2 phenotype in J774 murine and U937 human macrophages, and we measured expression of M1 and M2-markers. Interestingly, along with inhibiting the expression of M1-type markers, pinosylvin had an enhancing effect on the M2-type activation, shown as an increased expression of arginase-1 (Arg-1) and mannose receptor C type 1 (MRC1) in murine macrophages, and C-C motif chemokine ligands 17 and 26 (CCL17 and CCL26) in human macrophages. In IL-4-treated macrophages, pinosylvin enhanced PPAR-γ expression but had no effect on STAT6 phosphorylation. The results show, for the first time, that pinosylvin shifts macrophage polarization from the pro-inflammatory M1 phenotype towards M2 phenotype, supporting resolution of inflammation and repair.

Association of Microglia/macrophage Polarization With Perihematomal Edema and Clinical Outcome in Patients With Acute Intracerebral Hemorrhage

2021 ◽  
Author(s):  
Xue-Ming Shen ◽  
Xiu-Peng Han ◽  
Hong-Qi Xu ◽  
Yan-Jun Tang ◽  
Song Han ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Intracerebral Hemorrhage ◽  
Clinical Outcomes ◽  
Macrophage Activation ◽  
Macrophage Polarization ◽  
Treatment Decision ◽  
Wilcoxon Test ◽  
M1 Phenotype ◽  
Perihematomal Edema ◽  
M2 Phenotype

Abstract Background: Perihematomal edema (PHE) is a marker of secondary injury in intracerebral hemorrhage (ICH) and is associated with poor clinical outcomes. Microglial and macrophage activation, or their polarization could lead to a pro-inflammatory or anti-inflammatory response in stroke. However, little is known about the association between inflammatory cells and ICH. Thus, we characterized the inflammatory cell response, and assessed its association with parameters such as hematoma, PHE volume, and clinical outcome in patients with acute ICH.Methods: Fifty-two patients with acute ICH were retrospectively enrolled in our study. All patients underwent surgery, and brain tissue from the PHE was acquired. Immunofluorescence staining was performed to evaluate microglia (CD11b+/TMEM119+), macrophages (CD11b+/TMEM119-), and the M1 (MHC+/CD11b+) and M2 (CD206+/CD11b+) phenotypes. The relative PHE (r-PHE) was the main marker for assessing PHE volume. The Wilcoxon test and Spearman correlation analysis were the main statistical analysis methods used.Results: Microglia/macrophages, and their phenotypes were detected within 6 hours after stroke. Microglia and the M2 phenotype were negatively correlated with r-PHE, while macrophages and the M1 phenotype were positively correlated with r-PHE; however, these parameters were not associated with age, sex, or location. There was a positive correlation between the microglia and M2-phenotype levels (r = 0.443, p = 0.001) and between the macrophage and M1-phenotype levels (r = 0.458, p <0.001). Microglia (r = -0.295, p = 0.033) and M2-phenotype (r = -0.384, p = 0.005) levels were negatively correlated with the National Institutes of Health stroke scale (NIHSS) after treatment.Finally, using lasso Poisson regression models, we developed a score for predicting the NIHSS score after treatment. Decision curve analysis showed notable net benefits of this score.Conclusion: Microglial and macrophage activation, and their polarization were significantly associated with r-PHE and clinical outcomes in ICH, and could provide therapeutic insights for PHE management after hemorrhagic stroke.

scholarly journals Luteolin transforms the BMDM polarity to regulate the expression of inflammatory factors

2020 ◽  
Author(s):  
Shuxia Wang ◽  
Shuhang Xu ◽  
Meng Cao ◽  
Jing Zhou ◽  
Xiaodong Mao ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Macrophage Polarization ◽  
Membrane Surface ◽  
Inflammatory Factors ◽  
Mouse Bone Marrow ◽  
M2 Polarization ◽  
M1 Phenotype ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
M1 Type

ABSTRACTMacrophage are indispensable regulator cells in inflammatory response. Macrophage polarization and its secreted inflammatory factors have affinity with the outcomes of inflammation. Luteolin, a flavonoid abundant in plants has anti-inflammatory activity, but whether luteolin can manipulate M1/M2 polarization of BMDM to suppress inflammation is still veiled. The purpose of this study was to observe the effects of luterolin on the polarity of BMDM derived from C57BL/6 mice and the expression of inflammatory factors, to explore the mechanism of luteolin regulating the BMDM polarity. M1-polarized BMDM were induced by LPS+IFN-γ, M2-polarization were stimulated with IL-4. BMDM morphology was observed by laser confocal microscopy; levels of BMDM differentiation and CD11c or CD206 on membrane surface were assessed by FCM; mRNA and protein of M1/M2-type inflammatory factors were performed by qPCR and ELISA, respectively; the expression of p-STAT1 and p-STAT6 protein pathways was detected by Western-blotting. The isolated mouse bone marrow cells were successfully differentiated into BMDM, LPS+IFN-γ induced BMDM M1-phenotype polarization, and IL-4 induced its M2-phenotype polarization. After M1-polarized BMDM treated with luteolin, M1-type pro-inflammatory factors including IL-6, TNF-α□iNOS, CD86 were down-regulated while M2-type anti-inflammatory factors including IL-10, Arg1, CD206 were up-regulated; the expression of M1-type surface marker CD11c decreased, nevertheless, M2-type marker CD206 increased; levels of inflammatory signaling protein p-STAT1 and p-STAT6 were attenuated and enhanced respectively. Our study suggests luteolin may transform BMDM polarity through p-STAT1/6 to regulate the expression of inflammatory mediators, thereby inhibiting inflammation. Naturally occurring luteolin hold promise as an anti-inflammatory and immunomodulatory agent.

scholarly journals PTX-3 Secreted by Intra-Articular-Injected SMUP-Cells Reduces Pain in an Osteoarthritis Rat Model

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2420
Author(s):  
Minju Lee ◽  
Gee-Hye Kim ◽  
Miyeon Kim ◽  
Ji Min Seo ◽  
Yu Mi Kim ◽  
...  
Keyword(s):  
Scale Up ◽  
Therapeutic Effects ◽  
Arginase 1 ◽  
Inflammatory Phenotype ◽  
Monosodium Iodoacetate ◽  
M1 Phenotype ◽  
Interleukin 1Α ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Inflammatory Macrophages

Mesenchymal stem cells (MSCs) are accessible, abundantly available, and capable of regenerating; they have the potential to be developed as therapeutic agents for diseases. However, concerns remain in their further application. In this study, we developed a SMall cell+Ultra Potent+Scale UP cell (SMUP-Cell) platform to improve whole-cell processing, including manufacturing bioreactors and xeno-free solutions for commercialization. To confirm the superiority of SMUP-Cell improvements, we demonstrated that a molecule secreted by SMUP-Cells is capable of polarizing inflammatory macrophages (M1) into their anti-inflammatory phenotype (M2) at the site of injury in a pain-associated osteoarthritis (OA) model. Lipopolysaccharide-stimulated macrophages co-cultured with SMUP-Cells expressed low levels of M1-phenotype markers (CD11b, tumor necrosis factor-α, interleukin-1α, and interleukin-6), but high levels of M2 markers (CD163 and arginase-1). To identify the paracrine action underlying the anti-inflammatory effect of SMUP-Cells, we employed a cytokine array and detected increased levels of pentraxin-related protein-3 (PTX-3). Additionally, PTX-3 mRNA silencing was applied to confirm PTX-3 function. PTX-3 silencing in SMUP-Cells significantly decreased their therapeutic effects against monosodium iodoacetate (MIA)-induced OA. Thus, PTX-3 expression in injected SMUP-Cells, applied as a therapeutic strategy, reduced pain in an OA model.

Abstract 553: Siglec-1 (CD169) on Monocytes/Macrophages: A New Receptor For Extracellular Self-RNA in Triggering Inflammatory Responses via the Sheddase TACE/ADAM17

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Hector A Cabrera-Fuentes ◽  
Klaus T Preissner ◽  
William A Boisvert
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Transmembrane Protein ◽  
Macrophage Polarization ◽  
Extracellular Rna ◽  
Tnf Α ◽  
M1 Phenotype ◽  
Phenotype Markers ◽  
Anti Inflammatory

As an important component of atherosclerosis, monocytes/macrophages respond to external stimuli with rapid changes in their expression of many inflammation-related genes to undergo polarization towards the M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotype. Although sialoadhesin (Sn), also known as SIGLEC-1 or CD169, is a transmembrane protein receptor expressed on monocytes and macrophages whether it has a role in macrophage polarization and ultimately, macrophage-driven atherogenesis, has not been investigated. We have previously shown that, independently of Toll-like receptor signaling, extracellular RNA (eRNA) could exert pro-thrombotic and pro-inflammatory properties in the cardiovascular system by inducing cytokine mobilization. In the current study, recombinant mouse macrophage CSF[[Unable to Display Character: &#8211;]]driven bone marrow-derived macrophage (BMDM) differentiation was found to be skewed towards the M1 phenotype by exposure of cells to eRNA. This resulted in up-regulation of inflammatory markers, whereas anti-inflammatory genes were significantly down-regulated by eRNA. Interestingly, eRNA was released from BMDM under hypoxia and induced TNF-α liberation by activating TNF-α converting enzyme (TACE) to provoke inflammation. Conversely, TNF-α promoted eRNA release, especially under hypoxia, feeding a vicious cycle of cell damage. Administration of RNase1 or TAPI (a TACE-inhibitor) prevented the production of inflammatory mediators. Murine BMDM isolated from mice deficient in sialoadhesin had the opposite reaction to eRNA treatment with a prominent down-regulation of pro-inflammatory cytokines/M1 phenotype markers, while anti-inflammatory cytokines/M2 phenotype markers were significantly raised. In keeping with the proposed role of eRNA as a pro-inflammatory “alarm signal”, these data further shed light on the role of eRNA in macrophage function in the context of chronic inflammatory diseases such as atherosclerosis. The identification of sialoadhesin as putative eRNA recognition site on macrophages may allow further investigation of the underlying mechanisms of eRNA-macrophage interaction and related signal transduction pathways. Siglec-1 thereby may provides a new target to treat eRNA-mediated vascular diseases.

scholarly journals Asaronic Acid Inhibited Glucose-Triggered M2-Phenotype Shift Through Disrupting the Formation of Coordinated Signaling of IL-4Rα-Tyk2-STAT6 and GLUT1-Akt-mTOR-AMPK

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 2006
Author(s):  
Hyeongjoo Oh ◽  
Sin-Hye Park ◽  
Min-Kyung Kang ◽  
Yun-Ho Kim ◽  
Eun-Jung Lee ◽  
...  
Keyword(s):  
High Glucose ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Macrophage Polarization ◽  
Arginase 1 ◽  
M2 Polarization ◽  
Functional Transition ◽  
Functional Induction ◽  
M2 Phenotype ◽  
Functional Phenotype

Macrophage polarization has been implicated in the pathogenesis of metabolic diseases such as obesity, diabetes, and atherosclerosis. Macrophages responsiveness to polarizing signals can result in their functional phenotype shifts. This study examined whether high glucose induced the functional transition of M2 macrophages, which was inhibited by asaronic acid, one of purple perilla constituents. J774A.1 murine macrophages were incubated with 40 ng/mL interleukin (IL)-4 or exposed to 33 mM glucose in the presence of 1-20 μΜ asaronic acid. In macrophages treated with IL-4 for 48 h, asaronic acid further accelerated cellular induction of the M2 markers of IL-10, arginase-1, CD163, and PPARγ via increased IL-4-IL-4Rα interaction and activated Tyk2-STAT6 pathway. Asaronic acid promoted angiogenic and proliferative capacity of M2-polarized macrophages, through increasing expression of VEGF, PDGF, and TGF-β. In glucose-loaded macrophages, there was cellular induction of IL-4, IL-4 Rα, arginase-1, and CD163, indicating that high glucose skewed naïve macrophages toward M2 phenotypes via an IL-4-IL-4Rα interaction. However, asaronic acid inhibited M2 polarization in diabetic macrophages in parallel with inactivation of Tyk2-STAT6 pathway and blockade of GLUT1-mediated metabolic pathway of Akt-mTOR-AMPKα. Consequently, asaronic acid deterred functional induction of COX-2, CTGF, α-SMA, SR-A, SR-B1, and ABCG1 in diabetic macrophages with M2 phenotype polarity. These results demonstrated that asaronic acid allayed glucose-activated M2-phenotype shift through disrupting coordinated signaling of IL-4Rα-Tyk2-STAT6 in parallel with GLUT1-Akt-mTOR-AMPK pathway. Thus, asaronic acid has therapeutic potential in combating diabetes-associated inflammation, fibrosis, and atherogenesis through inhibiting glucose-evoked M2 polarization.

Targeted ferritin nanoparticle encapsulating CpG oligodeoxynucleotides induces tumor-associated macrophage M2 phenotype polarization into M1 phenotype and inhibits tumor growth

Nanoscale ◽  
2020 ◽  
Vol 12 (43) ◽  
pp. 22268-22280
Author(s):  
Hui Shan ◽  
Wenlong Dou ◽  
Yu Zhang ◽  
Mi Qi
Keyword(s):  
Tumor Growth ◽  
Intravenous Injection ◽  
Inhibit Tumor Growth ◽  
Cpg Oligodeoxynucleotides ◽  
Tumor Associated Macrophage ◽  
M1 Phenotype ◽  
M1 Type ◽  
M2 Phenotype

Novel M2pep-rHF-CpG nanoparticles repolarize the M2-type TAMs to M1-type and inhibit tumor growth after intravenous injection.

scholarly journals The Degree of Helicobacter pylori Infection Affects the State of Macrophage Polarization through Crosstalk between ROS and HIF-1α

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Ying Lu ◽  
Jianfang Rong ◽  
Yongkang Lai ◽  
Li Tao ◽  
Xiaogang Yuan ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Macrophage Polarization ◽  
Polarization State ◽  
Hypoxia Inducible Factor ◽  
Mtor Pathway ◽  
Raw 264.7 Cells ◽  
Gastric Lesions ◽  
M1 Phenotype ◽  
H Pylori ◽  
M2 Phenotype

Background and Objective. Helicobacter pylori (H. pylori) is involved in macrophage polarization, but the specific mechanism is not well understood. Therefore, this study is aimed at investigating the effects of the degree of H. pylori infection on the macrophage polarization state and the crosstalk between reactive oxygen species (ROS) and hypoxia-inducible factor 1 α (HIF-1α) in this process. Methods. The expression of CD86, CD206, and HIF-1α in the gastric mucosa was evaluated through immunohistochemistry. RAW 264.7 cells were cocultured with H. pylori at various multiplicities of infection (MOIs), and iNOS, CD86, Arg-1, CD206, and HIF-1α expression was detected by Western blot, PCR, and ELISA analyses. ROS expression was detected with the fluorescent probe DCFH-DA. Macrophages were also treated with the ROS inhibitor NAC or HIF-1α inhibitor YC-1. Results. Immunohistochemical staining revealed that the macrophage polarization state was associated with the progression of gastric lesions and state of H. pylori infection. The MOI of H. pylori affected macrophage polarization, and H. pylori enhanced the expression of ROS and HIF-1α in macrophages. A low MOI of H. pylori promoted both the M1 and M2 phenotypes, while a high MOI suppressed the M2 phenotype. Furthermore, ROS inhibition attenuated HIF-1α expression and switched macrophage polarization from M1 to M2. However, HIF-1α inhibition suppressed ROS expression and inhibited both the M1 phenotype and the M2 phenotype. Inhibition of ROS or HIF-1α also suppressed the activation of the Akt/mTOR pathway, which was implicated in H. pylori-induced macrophage polarization. Conclusions. Macrophage polarization is associated with the progression of gastric lesions and state of H. pylori infection. The MOI of H. pylori influences the macrophage polarization state. Crosstalk between ROS and HIF-1α regulates H. pylori-induced macrophage polarization via the Akt/mTOR pathway.

scholarly journals Netrin-1-treated macrophages protect the kidney against ischemia-reperfusion injury and suppress inflammation by inducing M2 polarization

2013 ◽  
Vol 304 (7) ◽  
pp. F948-F957 ◽  
Author(s):  
Punithavathi Vilapakkam Ranganathan ◽  
Calpurnia Jayakumar ◽  
Ganesan Ramesh
Keyword(s):  
Reperfusion Injury ◽  
Macrophage Activation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Kidney Injury ◽  
In Vitro Studies ◽  
Arginase 1 ◽  
M2 Polarization

Improper macrophage activation is pathogenically linked to various metabolic, inflammatory, and immune disorders. Therefore, regulatory proteins controlling macrophage activation have emerged as important new therapeutic targets. We recently demonstrated that netrin-1 regulates inflammation and infiltration of monocytes and ameliorates ischemia-reperfusion-induced kidney injury. However, it was not known whether netrin-1 regulates the phenotype of macrophages and the signaling mechanism through which it might do this. In this study, we report novel mechanisms underlying netrin-1's effects on macrophages using in vivo and in vitro studies. Overexpression of netrin-1 in spleen and kidney of transgenic mice increased expression of arginase-1, IL-4, and IL-13 and decreased expression of COX-2, indicating a phenotypic switch in macrophage polarization toward an M2-like phenotype. Moreover, flow cytometry analysis showed a significant increase in mannose receptor-positive macrophages in spleen compared with wild type. In vitro, netrin-1 induced the expression of M2 marker expression in bone marrow-derived macrophages, peritoneal macrophages, and RAW264.7 cells, and suppressed IFNγ-induced M1 polarization and production of inflammatory mediators. Adoptive transfer of netrin-1-treated macrophages suppressed inflammation and kidney injury against ischemia-reperfusion. Netrin-1 activated PPAR pathways and inhibition of PPAR activation abolished netrin-1-induced M2 polarization and suppression of cytokine production. Consistent with in vitro studies, administration of PPAR antagonist to mice abolished the netrin-1 protective effects against ischemia-reperfusion injury of the kidney. These findings illustrate that netrin-1 regulates macrophage polarization through PPAR pathways and confers anti-inflammatory actions in inflammed kidney tissue.

scholarly journals Dual Role of Hepatic Macrophages in the Establishment of the Echinococcus multilocularis Metacestode in Mice

2021 ◽  
Vol 11 ◽  
Author(s):  
Hui Wang ◽  
Chuan-Shan Zhang ◽  
Bin-Bin Fang ◽  
Jiao Hou ◽  
Wen-Ding Li ◽  
...  
Keyword(s):  
Echinococcus Multilocularis ◽  
Liver Tissue ◽  
Parasite Burden ◽  
Dual Role ◽  
M2 Macrophages ◽  
Hepatic Macrophages ◽  
M1 Phenotype ◽  
Anti Inflammatory ◽  
M2 Phenotype

Echinococcus multilocularis larvae, predominantly located in the liver, cause a tumor-like parasitic disease, alveolar echinococcosis (AE), that is characterized by increased infiltration of various immune cells, including macrophages, around the lesion that produces an “immunosuppressive” microenvironment, favoring its persistent infection. However, the role of hepatic macrophages in the host defense against E. multilocularis infection remains poorly defined. Using human liver tissues from patients with AE and a hepatic experimental mouse model of E. multilocularis, we investigated the phenotype and function of hepatic macrophages during the parasite infection. In the present study, we found that a large number of CD68+ macrophages accumulated around the metacestode lesion in the liver of human AE samples and that both S100A9+ proinflammatory (M1 phenotype) and CD163+ anti-inflammatory (M2 phenotype) macrophages were significantly higher in close liver tissue (CLT) than in distant liver tissue (DLT), whereas M2 macrophages represent the dominant macrophage population. Furthermore, E. multilocularis-infected mice exhibited a massive increase in macrophage (F4/80+) infiltration in the liver as early as day 5, and the infiltrated macrophages were mainly monocyte-derived macrophages (CD11bhi F4/80int MoMFs) that preferentially differentiated into the M1 phenotype (iNOS+) at the early stage of E. multilocularis infection and then polarized to anti-inflammatory macrophages of the M2 phenotype (CD206+) at the chronic stage of infection. We further showed that elimination of macrophages by treatment of mice with clodronate-liposomes before E. multilocularis infection impaired worm expulsion and was accompanied by a reduction in liver fibrosis, yielding a high parasite burden. These results suggest that hepatic macrophages may play a dual role in the establishment and development of E. multilocularis metacestodes in which early larvae clearance is promoted by M1 macrophages while persistent metacestode infection is favored by M2 macrophages.

scholarly journals The inflammatory role of dysregulated IRS2 in pulmonary vascular remodeling under hypoxic conditions

2021 ◽  
Author(s):  
Mayumi Nakahara ◽  
Homare Ito ◽  
John T Skinner ◽  
Qing Lin ◽  
Rasa Tamosiuniene ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Signaling Pathway ◽  
Vascular Remodeling ◽  
Macrophage Activation ◽  
Ventricular Hypertrophy ◽  
Right Ventricular Hypertrophy ◽  
Activation Markers ◽  
Pulmonary Vascular Remodeling ◽  
Arginase 1 ◽  
Anti Inflammatory

Pulmonary hypertension (PH) is a devastating disease characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown previously that insulin receptor substrate 2 (IRS2), a molecule highly critical to insulin resistance and metabolism, has an anti-inflammatory role in Th2-skewed lung inflammation and pulmonary vascular remodeling. Here, we investigated the hypothesis that IRS2 has an immunomodulatory role in human and experimental PH. Expression analysis showed that IRS2 was significantly decreased in the pulmonary vasculature of patients with pulmonary arterial hypertension and in rat models of PH. In mice, genetic ablation of IRS2 enhanced the hypoxia-induced signaling pathway of Akt and Forkhead box O1 (FOXO1) in the lung tissue and increased pulmonary vascular muscularization, proliferation, and perivascular macrophage recruitment. Furthermore, mice with homozygous IRS2 gene deletion showed a significant gene dosage-dependent increase in pulmonary vascular remodeling and right ventricular hypertrophy in response to hypoxia. Functional studies with bone marrow-derived macrophages isolated from homozygous IRS2 gene-deleted mice showed that hypoxia exposure led to enhancement of the Akt and ERK signaling pathway followed by increases in the pro-PH macrophage activation markers vascular endothelial growth factor-A and arginase 1. Our data suggest that IRS2 contributes to anti-inflammatory effects by regulating macrophage activation and recruitment, which may limit the vascular inflammation, remodeling, and right ventricular hypertrophy that are seen in PH pathology. Restoring the IRS2 pathway may be an effective therapeutic approach for the treatment of PH and right heart failure.

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