scholarly journals Interleukin‐4 repairs wear particle induced osteolysis by modulating macrophage polarization and bone turnover

2020 ◽  
Author(s):  
Jukka Pajarinen ◽  
Tzuhua Lin ◽  
Akira Nabeshima ◽  
Taishi Sato ◽  
Emmanuel Gibon ◽  
...  
Keyword(s):  
Bone Turnover ◽  
Macrophage Polarization ◽  
Wear Particle ◽  
Interleukin 4

Abstract 112: Myeloid Mineralocorticoid Receptor Controls Inflammatory and Fibrotic Responses After Renal Ischemic Injury via Macrophage Interleukin-4 Receptor

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Jonatan Barrera-Chimal ◽  
Sebastian M Lechner ◽  
Soumaya E Moghrabi ◽  
Peter Kolkhof ◽  
Frédéric Jaisser
Keyword(s):  
Mineralocorticoid Receptor ◽  
De Novo ◽  
Interstitial Fibrosis ◽  
Macrophage Polarization ◽  
Peritoneal Macrophages ◽  
Renal Ischemia ◽  
Receptor Expression ◽  
Interleukin 4 ◽  
Mrna Levels ◽  
Kidney Fibrosis

Introduction: Patients who survive an episode of acute kidney injury (AKI) are at high risk of de novo chronic kidney disease (CKD) development. Pharmacological mineralocorticoid receptor (MR) antagonism is useful to prevent CKD after a single episode of ischemic AKI in the rat. Objective: Test the involvement of myeloid MR in the development of kidney fibrosis after an ischemic AKI episode. Methods: We included 18 male C57/B6 mice that were divided in: sham, renal ischemia for 22.5 min and IR plus treatment with the non-steroidal MR antagonist finerenone (10 mg/kg) at -48, -24 and -1 h before IR. MR inactivation in myeloid cells (MR MyKO ) was achieved by crossing mice with the MR alleles flanked by loxP sites (MR f/f ) with mice expressing the Cre recombinase under the LysM promoter activity. In MR f/f and MR MyKO mice we induced renal IR of 22.5 min or sham surgery. The mice were followed-up during 4 weeks to test for AKI to CKD transition. In another set of mice, the macrophages were sorted from kidneys after 24 h of reperfusion and flow cytometry characterization or mRNA extraction was performed. Thyoglycolate elicited peritoneal macrophages were used for in vitro studies. Results: The progression of AKI to CKD after 4 weeks of renal ischemia in the untreated C57/B6 and MR f/f mice was characterized by a 50% increase in plasma creatinine, a 2-fold increase in the mRNA levels of TGF-β and fibronectin as well as by severe tubule-interstitial fibrosis. The mice that received finerenone or MR MyKO mice were protected against these alterations. Increased expression of M2-anti-inflamatory markers in kidney-isolated macrophages from finerenone-treated or MR MyKO mice was observed. The inflammatory population of Ly6C high macrophages was reduced by 50%. In peritoneal macrophages in culture, MR inhibition promoted increased IL-4 receptor expression and activation, facilitating macrophage polarization to an M2 phenotype. Conclusion: MR antagonism or myeloid MR deficiency facilitates macrophage polarization to a M2, anti-inflammatory phenotype after kidney IR, preventing maladaptive repair and chronic kidney fibrosis and dysfunction. MR inhibition acts through the modulation of IL-4 receptor signaling to facilitate macrophage phenotype switching.

scholarly journals NF-κB/let-7f-5p/IL-10 pathway involves in wear particle-induced osteolysis by inducing M1 macrophage polarization

Cell Cycle ◽  
2018 ◽  
Vol 17 (17) ◽  
pp. 2134-2145 ◽  
Author(s):  
Xu-ren Gao ◽  
Jian Ge ◽  
Wei-yi Li ◽  
Wang-chen Zhou ◽  
Lei Xu ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Wear Particle ◽  
M1 Macrophage

Interleukin-4-Clicked Surfaces Drive M2 Macrophage Polarization

ChemBioChem ◽  
2016 ◽  
Vol 17 (22) ◽  
pp. 2123-2128 ◽  
Author(s):  
Tessa Lühmann ◽  
Valerie Spieler ◽  
Vera Werner ◽  
Marie-Gabrielle Ludwig ◽  
Juliane Fiebig ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Interleukin 4 ◽  
M2 Macrophage ◽  
M2 Macrophage Polarization

Harnessing the immune response to improve functional healing

2018 ◽  
Vol 10 (463) ◽  
pp. eaav3889 ◽  
Author(s):  
Julianne L. Holloway
Keyword(s):  
Immune Response ◽  
Gold Nanoparticles ◽  
Mouse Model ◽  
Macrophage Polarization ◽  
Interleukin 4 ◽  
M2 Macrophage ◽  
Muscle Recovery ◽  
M2 Macrophage Polarization

Interleukin-4–conjugated gold nanoparticles promote M2 macrophage polarization and functional muscle recovery in an ischemic mouse model.

scholarly journals The USP14–NLRC5 pathway inhibits titanium particle–induced osteolysis in mice by suppressing NF-κB and PI3K/AKT activities

2020 ◽  
Vol 295 (20) ◽  
pp. 7018-7032 ◽  
Author(s):  
Guibin Fang ◽  
Yuan Fu ◽  
Shixun Li ◽  
Junxiong Qiu ◽  
Manyuan Kuang ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Wear Particle ◽  
Wear Particles ◽  
Titanium Particle ◽  
Pathway Activation ◽  
M1 Macrophage ◽  
Phosphoinositide 3 Kinase ◽  
Factor Α

Total hip arthroplasty (THA) is a widely-used surgical intervention for treating patients with end-stage degenerative and inflammatory osteoarthropathy. However, wear particles from the artificial titanium joint can induce osteolysis, limiting the long-term survivorship of THA. Monocyte/macrophage lineage cells are the key players in the response to wear particles, and the proinflammatory NF-κB and phosphoinositide 3-kinase (PI3K)–AKT Ser/Thr kinase (AKT)-signaling pathways have been shown to be the most important contributors to wear particle–induced osteolysis. In contrast, ubiquitin-specific protease 14 (USP14) specifically removes the polyubiquitin chains from the nucleotide-binding and oligomerization domain (NOD)-like receptor family Caspase recruitment domain (CARD)–containing 5 (NLRC5) and thereby enhances the NLRC5-mediated inhibition of NF-κB signaling. In this study, we aimed to clarify the role of the USP14–NLRC5 pathway in wear particle–induced osteolysis in vitro and in vivo. We found that NLRC5 or USP14 overexpression inhibits titanium particle–induced proinflammatory tumor necrosis factor α (TNFα) production and NF-κB pathway activation, and it also decreases M1 macrophage polarization and PI3K/AKT pathway activation. Of note, NLRC5 and USP14 overexpression attenuated titanium particle–induced cranial osteolysis in mice. In conclusion, the findings of our study indicate that the USP14–NLRC5 pathway inhibits titanium particle–induced osteolysis by suppressing the NF-κB and PI3K/AKT pathways both in vitro and in vivo.

scholarly journals S100A4 enhances protumor macrophage polarization by control of PPAR-γ-dependent induction of fatty acid oxidation

2021 ◽  
Vol 9 (6) ◽  
pp. e002548
Author(s):  
Shuangqing Liu ◽  
Huilei Zhang ◽  
Yanan Li ◽  
Yana Zhang ◽  
Yangyang Bian ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fluorescent Protein ◽  
Macrophage Polarization ◽  
Interleukin 4 ◽  
Whole Body ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Macrophage Phenotype ◽  
Ppar Γ

BackgroundThe peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent upregulation of fatty acid oxidation (FAO) mediates protumor (also known as M2-like) polarization of tumor-associated macrophages (TAMs). However, upstream factors determining PPAR-γ upregulation in TAM protumor polarization are not fully identified. S100A4 plays crucial roles in promotion of cancer malignancy and mitochondrial metabolism. The fact that macrophage-derived S100A4 is major source of extracellular S100A4 suggests that macrophages contain a high abundance of intracellular S100A4. However, whether intracellular S100A4 in macrophages also contributes to cancer malignancy by enabling TAMs to acquire M2-like protumor activity remains unknown.MethodsGrowth of tumor cells was evaluated in murine tumor models. TAMs were isolated from the tumor grafts in whole-body S100A4-knockout (KO), macrophage-specific S100A4-KO and transgenic S100A4WT−EGFP mice (expressing enhanced green fluorescent protein (EGFP) under the control of the S100A4 promoter). In vitro induction of macrophage M2 polarization was conducted by interleukin 4 (IL-4) stimulation. RNA-sequencing, real-time quantitative PCR, flow cytometry, western blotting, immunofluorescence staining and mass spectrometry were used to determine macrophage phenotype. Exogenous and endogenous FAO, FA uptake and measurement of lipid content were used to analyze macrophage metabolism.ResultsTAMs contain two subsets based on whether they express S100A4 or not and that S100A4+ subsets display protumor phenotypes. S100A4 can be induced by IL-4, an M2 activator of macrophage polarization. Mechanistically, S100A4 controls the upregulation of PPAR-γ, a transcription factor required for FAO induction during TAM protumor polarization. In S100A4+ TAMs, PPAR-γ mainly upregulates CD36, a FA transporter, to enhance FA absorption as well as FAO. In contrast, S100A4-deficient TAMs exhibited decreased protumor activity because of failure in PPAR-γ upregulation-dependent FAO induction.ConclusionsWe find that macrophagic S100A4 enhances protumor macrophage polarization as a determinant of PPAR-γ-dependent FAO induction. Accordingly, our findings provide an insight into the general mechanisms of TAM polarization toward protumor phenotypes. Therefore, our results strongly suggest that targeting macrophagic S100A4 may be a potential strategy to prevent TAMs from re-differentiation toward a protumor phenotype.

scholarly journals Effect of Cytokine Interplay on Macrophage Polarization during Chronic Pulmonary Infection with Cryptococcus neoformans

2011 ◽  
Vol 79 (5) ◽  
pp. 1915-1926 ◽  
Author(s):  
Shikha Arora ◽  
Michal A. Olszewski ◽  
Tiffany M. Tsang ◽  
Roderick A. McDonald ◽  
Galen B. Toews ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Cryptococcus Neoformans ◽  
Pulmonary Infection ◽  
Macrophage Polarization ◽  
Polarization State ◽  
Interleukin 4 ◽  
Activation Markers ◽  
Content Type ◽  
Th1 And Th2 Cytokines ◽  
Ifn Γ

ABSTRACTThe immune response toCryptococcus neoformansfollowing pulmonary infection of C57BL/6 wild-type (WT) mice results in the development of persistent infection with characteristics of allergic bronchopulmonary mycosis (ABPM). To further clarify the role of Th1/Th2 polarizing cytokines in this model, we performed kinetic analysis of cytokine responses and compared cytokine profiles, pathologies, and macrophage (Mac) polarization status inC. neoformans-infected WT, interleukin-4-deficient (IL-4−/−), and gamma interferon-deficient (IFN-γ−/−) C57BL/6 mice. Results show that cytokine expression in the infected WT mice is not permanently Th2 biased but changes dynamically over time. Using multiple Mac activation markers, we further demonstrate that IL-4 and IFN-γ regulate the polarization state of Macs in this model. A higher IL-4/IFN-γ ratio leads to the development of alternatively activated Macs (aaMacs), whereas a higher IFN-γ/IL-4 ratio leads to the generation of classically activated Macs (caMacs). WT mice that coexpress IL-4 and IFN-γ during fungal infection concurrently display both types of Mac polarization markers. Concurrent stimulation of Macs with IFN-γ and IL-4 results in an upregulation of both sets of markers within the same cells, i.e., formation of an intermediate aaMac/caMac phenotype. These cells express both inducible nitric oxide synthase (important for clearance) and arginase (associated with chronic/progressive infection). Together, our data demonstrate that the interplay between Th1 and Th2 cytokines supports chronic infection, chronic inflammation, and the development of ABPM pathology inC. neoformans-infected lungs. This cytokine interplay modulates Mac differentiation, including generation of an intermediate caMac/aaMac phenotype, which in turn may support chronic “steady-state” fungal infection and the resultant ABPM pathology.

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