Inhaled silica nanoparticles exacerbate atherosclerosis through skewing macrophage polarization towards M1 phenotype

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: –]]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.

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/5281795 ◽

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.

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Advanced Glycation End Products Enhance Macrophages Polarization into M1 Phenotype through Activating RAGE/NF-κB Pathway

BioMed Research International ◽

10.1155/2015/732450 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 49

Author(s):

Xian Jin ◽

Tongqing Yao ◽

Zhong’e Zhou ◽

Jian Zhu ◽

Song Zhang ◽

...

Keyword(s):

Advanced Glycation End Products ◽

Macrophage Polarization ◽

M2 Macrophage ◽

Advanced Glycation ◽

Alternatively Activated Macrophages ◽

M1 Macrophage ◽

Glycation End Products ◽

End Products ◽

Patients With Diabetes ◽

M1 Phenotype

Atherosclerotic lesions are accelerated in patients with diabetes. M1 (classically activated in contrast to M2 alternatively activated) macrophages play key roles in the progression of atherosclerosis. Since advanced glycation end products (AGEs) are major pathogenic factors and active inflammation inducers in diabetes mellitus, this study assessed the effects of AGEs on macrophage polarization. The present study showed that AGEs significantly promoted macrophages to express IL-6 and TNF-α. M1 macrophage markers such as iNOS and surface markers including CD11c and CD86 were significantly upregulated while M2 macrophage markers such as Arg1 and CD206 remained unchanged after AGEs stimulation. AGEs significantly increased RAGE expression in macrophages and activated NF-κB pathway, and the aforementioned effects were partly abolished by administration of anti-RAGE antibody or NF-κB inhibitor PDTC. In conclusion, our results suggest that AGEs enhance macrophage differentiation into proinflammatory M1 phenotype at least partly via RAGE/NF-κB pathway activation.

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Myeloid Sirtuin 6 Deficiency Causes Insulin Resistance in High-Fat Diet–Fed Mice by Eliciting Macrophage Polarization Toward an M1 Phenotype

Diabetes ◽

10.2337/db16-1446 ◽

2017 ◽

Vol 66 (10) ◽

pp. 2659-2668 ◽

Cited By ~ 38

Author(s):

Youngyi Lee ◽

Sun-O Ka ◽

Hye-Na Cha ◽

Yu-Na Chae ◽

Mi-Kyung Kim ◽

...

Keyword(s):

Insulin Resistance ◽

High Fat Diet ◽

Macrophage Polarization ◽

High Fat ◽

M1 Phenotype

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Yersinia pseudotuberculosis YopJ Limits Macrophage Response by Downregulating COX-2-Mediated Biosynthesis of PGE2 in a MAPK/ERK-Dependent Manner

Microbiology Spectrum ◽

10.1128/spectrum.00496-21 ◽

2021 ◽

Author(s):

Austin E. F. Sheppe ◽

John Santelices ◽

Daniel M. Czyz ◽

Mariola J. Edelmann

Keyword(s):

Bacterial Infection ◽

Yersinia Pseudotuberculosis ◽

Macrophage Polarization ◽

Inflammasome Activation ◽

Dependent Manner ◽

Macrophage Response ◽

M1 Phenotype ◽

Cox 2 ◽

Pathogen Clearance

PGE2 is a critical immunomodulatory lipid, but its role in bacterial infection and pathogen clearance is poorly understood. We previously demonstrated that PGE2 leads to macrophage polarization toward the M1 phenotype and stimulates inflammasome activation in infected macrophages.

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LncGBP9/miR-34a axis drives macrophages toward a phenotype conducive for spinal cord injury repair via STAT1/STAT6 and SOCS3

10.21203/rs.2.19759/v3 ◽

2020 ◽

Author(s):

Jiahui Zhou ◽

Zhiyue Li ◽

Tianding Wu ◽

Qun Zhao ◽

Qiancheng Zhao ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Macrophage Polarization ◽

Cytokine Signaling ◽

Secondary Injury ◽

Protein Levels ◽

M2 Polarization ◽

Cord Injury ◽

Socs3 Expression ◽

M1 Phenotype

Abstract Background: Acute spinal cord injury (SCI) could cause mainly two types of pathological sequelae, the primary mechanical injury, and the secondary injury. The macrophage in SCI are skewed toward the M1 phenotype that might cause the failure to post-SCI repair. Methods: SCI model was established in Balb/c mice, and the changes in macrophage phenotypes after SCI were monitored. Bioinformatic analyses were performed to select factors that might regulate macrophage polarization after SCI. Mouse bone marrow-derived macrophages ( BMDMs ) were isolated, identified, and induced for M1 or M2 polarization; the effects of lncRNA guanylate binding protein-9 (lnc GBP9 ) and suppressor of cytokine signaling 3 (SOCS 3) on macrophages polarization were examined in vitro and in vivo . The predicted miR-34a binding to lncGBP9 and SOCS3 was validated; the dynamic effects of lncGBP9 and miR-34a on SOCS3, signal transducer and activator of transcription 1 (STAT 1) /STAT6 signaling, and macrophage polarization were examined. Finally, we investigated whether STAT6 could bind the miR-34a promoter to activate its transcription. Results: In SCI Balb/c mice, macrophage skewing toward M1 phenotypes was observed after SCI. In M1 macrophages, lncGBP9 silencing significantly decreased p-STAT1 and SOCS3 expression and protein levels, as well as the production of Interleukin (IL)-6 and IL-12; in M2 macrophages, lncGBP9 overexpression increased SOCS3 mRNA expression and protein levels while suppressed p-STAT6 levels and the production of IL-10 and transforming growth factor-beta 1 (TGF-β1 ) , indicating that lncGBP9 overexpression promotes the M1 polarization of macrophages. In lncGBP9-silenced SCI mice, the M2 polarization was promoted on day 28 after the operation, further indicating that lncGBP9 silencing revised the predominance of M1 phenotype at the late stage of secondary injury after SCI, therefore improving the repair after SCI. IncGBP9 competed with SOCS3 for miR-34a binding to counteract miR-34a-mediated suppression on SOCS3 and then modulated STAT1/STAT6 signaling and the polarization of macrophages. STAT6 bound the promoter of miR-34a to activate its transcription. Conclusions: In macrophages, lncGBP9 sponges miR-34a to rescue SOCS3 expression, therefore modulating macrophage polarization through STAT1/STAT6 signaling. STAT6 bound the promoter of miR-34a to activate its transcription, thus forming two different regulatory loops to modulate the phenotype of macrophages after SCI.

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The observed difference of macrophage phenotype on different surface roughness of mineralized collagen

Regenerative Biomaterials ◽

10.1093/rb/rbz053 ◽

2020 ◽

Vol 7 (2) ◽

pp. 203-211 ◽

Cited By ~ 1

Author(s):

Jun Li ◽

Yu-Jue Zhang ◽

Zhao-Yong Lv ◽

Kun Liu ◽

Chun-Xiu Meng ◽

...

Keyword(s):

Surface Roughness ◽

Tissue Regeneration ◽

Macrophage Polarization ◽

Inflammatory Factor ◽

Macrophage Phenotype ◽

Factors Affecting ◽

M1 Phenotype ◽

High Level ◽

Factor Α ◽

Mineralized Collagen

Abstract Biomaterials regulate macrophages and promote regeneration function, which is a new hot pot in tissue engineering and regenerative medicine. The research based on macrophage materials biology has appeared happy future, but related research on regulating macrophages and promoting tissue regeneration is still in its infancy. The surface roughness of biomaterials is one of the important factors affecting macrophage behavior. Previous study also found that the surface roughness of many biomaterials regulating macrophage polarization, but not including mineralized collagen (MC). In this study, we designed and fabricated MC with different roughness and investigated the influence of MC with different roughness on macrophages. In the study, we found that on the rough surface of MC, macrophages exhibited M1 phenotype-amoeboid morphology and high-level secretory of inflammatory factor (tumor necrosis factor-α and interleukin-6), while smoother surface exhibited M2 phenotype. These data will be beneficial to understand the mechanism deeply and enrich biomaterials tissue regeneration theory, provide a new train of thought biomaterials inducing tissue regeneration and repair and guide the optimum design of new biomaterials, development and reasonable applications.

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