Integrin αM promotes macrophage alternative M2 polarization in hyperuricemia-related chronic kidney disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1092994 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28487609_1.fastq.gz | Fastqsanger.gz | |||
| SRR28487609_2.fastq.gz | Fastqsanger.gz | |||
| SRR28487610_1.fastq.gz | Fastqsanger.gz | |||
| SRR28487610_2.fastq.gz | Fastqsanger.gz | |||
| SRR28487611_1.fastq.gz | Fastqsanger.gz |
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Project description:Hyperuricemia is an essential risk factor in chronic kidney disease (CKD), while urate-lowering therapy to prevent or delay CKD is controversial. Alternatively activated macrophages in response to local microenvironment play diverse roles in kidney diseases. Here, we aim to investigate whether and how macrophage integrin αM (ITGAM) contributes to hyperuricemia-related CKD. In vivo, we explored dynamic characteristics of renal tissue in C57BL/6J mice with hyperuricemia-related CKD. By incorporating transcriptomics and phosphoproteomics data, we analyzed gene expression profile, hub genes and potential pathways. In vitro, we validated bioinformatic findings under different conditions with interventions corresponding to core nodes. We found that hyperuricemia-related CKD was characterized by elevated serum uric acid levels, impaired renal function, activation of macrophage alternative (M2) polarization, and kidney fibrosis. Integrated bioinformatic analyses revealed Itgam as the potential core gene and was associated with focal adhesion signaling. Notably, we confirmed the upregulated expression of macrophage ITGAM, activated pathway, and macrophage M2 polarization in injured kidneys. In vitro, through silencing Itgam, inhibiting p-FAK or p-AKT1 phosphorylation, and concurrent inhibiting of p-FAK while activating p-AKT1 all contributed to the modulation of macrophage M2 polarization. Our results indicated targeting macrophage ITGAM might be a promising therapeutic approach for preventing CKD.
2024-06-26 | GSE262687 | GEO
Project description:The proteasome is a central regulatory hub for intracellular signaling by degrading numerous signaling mediators. Immunoproteasomes are specialized types of proteasomes known to be involved in shaping adaptive immune responses, but their role for innate immune signaling is elusive. Here, we analyzed immunoproteasome function for polarization of alveolar macrophages which are highly specialized tissue macrophages of the alveolar surface of the lung. Classical activation (M1 polarization) of primary alveolar macrophages by LPS/IFNγ transcriptionally induced all three immunoproteasome subunits LMP2, LMP7, and MECL-1. In contrast, IL-4 triggered alternative (M2) activation was accompanied by posttranscriptional upregulation of LMP2 and LMP7. Accordingly, immunoproteasome activity increased in M1 cells, and to some extent under M2 conditions. Analyzing the polarization capability from LMP7 deficient mice revealed no effect on the LPS/IFNγ triggered M1 profile, but uncovered a distorted M2 profile for IL-4 stimulated LMP7-/- alveolar macrophages as characterized by increased M2 marker gene expression and CCL17 cytokine release. This shift in immunoproteasome-dependent M2 polarization was accompanied by amplified AKT/STAT6 activation and IRF4 expression in LMP7-/- alveolar macrophages. IL-13 stimulation of LMP7 deficient cells induced a similar M2 skewed profile and IL4Rα protein expression was generally elevated in LMP7-/- alveolar macrophages, indicating that amplified IL4R signaling in immunoproteasome defective cells may contribute to augmented M2 polarization. Importantly, treatment with an LMP7-specific proteasome inhibitor recapitulated the findings of genetic LMP7 inactivation. Our results thus suggest a novel role of immunoproteasome function for regulating innate immune function of macrophages by limiting IL4R expression and signaling. Expression data of M0 and M2 macrophages derived from Lmp7 k.o. and control animals
2016-06-29 | E-GEOD-72000 | biostudies-arrayexpress
Project description:In response to microenvironmental signals macrophages undergo different activation, indicated as classic/M1 and alternative/M2 polarization. C-Myc transcription factor could be an essential player in M2 polarization. Functional relevance of c-Myc in M2 macrophage biology is investigated by evaluating the effect of 100-58F4, on the transcriptional profile induced on human macrophages by IL-4. Human monocytes were obtained from normal donor buffy coats by two-step gradient centrifugation using Ficoll (Biochrom) and Percoll (Amersham). Non-adherent cells were discarded, and the purified monocytes were incubated for 7 days in RPMI 1640 (Biochom) supplemented with 10% FCS (HyClone) and 100 ng/mL M-CSF to obtain resting macrophages. Macrophage polarization was obtained by removing the culture medium and culturing cells in RPMI 1640 supplemented with 10% FCS and 100 ng/mL LPS plus 20 ng/mL IFN-gamma (M1 polarization) or 20 ng/mL IL-4 (M2 polarization) for 24 h. When needed, chemical inhibitors were added with IL-4.
2011-09-15 | E-GEOD-32164 | biostudies-arrayexpress
Project description:In response to microenvironmental signals macrophages undergo different activation, indicated as classic/M1 and alternative/M2 polarization. C-Myc transcription factor could be an essential player in M2 polarization. Functional relevance of c-Myc in M2 macrophage biology is investigated by evaluating the effect of 100-58F4, on the transcriptional profile induced on human macrophages by IL-4.
2011-09-16 | GSE32164 | GEO
Project description:Hyperuricemia is an essential risk factor in chronic kidney disease (CKD), while urate-lowering therapy to prevent or delay CKD is controversial. Alternatively activated macrophages in response to local microenvironment play diverse roles in kidney diseases. Here, we aim to investigate whether and how macrophage integrin αM (ITGAM) contributes to hyperuricemia-related CKD. In vivo, we explored dynamic characteristics of renal tissue in hyperuricemia-related CKD mice. By incorporating transcriptomics and phosphoproteomics data, we analyzed gene expression profile, hub genes and potential pathways. In vitro, we validated bioinformatic findings under different conditions with interventions corresponding to core nodes. We found that hyperuricemia-related CKD was characterized by elevated serum uric acid levels, impaired renal function, activation of macrophage alternative (M2) polarization, and kidney fibrosis. Integrated bioinformatic analyses revealed Itgam as the potential core gene, which was associated with focal adhesion signaling. Notably, we confirmed the upregulated expression of macrophage ITGAM, activated pathway, and macrophage M2 polarization in injured kidneys. In vitro, through silencing Itgam, inhibiting p-FAK or p-AKT1 phosphorylation, and concurrent inhibiting of p-FAK while activating p-AKT1 all contributed to the modulation of macrophage M2 polarization. Our results indicated targeting macrophage ITGAM might be a promising therapeutic approach for preventing CKD.
| S-EPMC11193137 | biostudies-literature
Project description:The proteasome is a central regulatory hub for intracellular signaling by degrading numerous signaling mediators. Immunoproteasomes are specialized types of proteasomes known to be involved in shaping adaptive immune responses, but their role for innate immune signaling is elusive. Here, we analyzed immunoproteasome function for polarization of alveolar macrophages which are highly specialized tissue macrophages of the alveolar surface of the lung. Classical activation (M1 polarization) of primary alveolar macrophages by LPS/IFNγ transcriptionally induced all three immunoproteasome subunits LMP2, LMP7, and MECL-1. In contrast, IL-4 triggered alternative (M2) activation was accompanied by posttranscriptional upregulation of LMP2 and LMP7. Accordingly, immunoproteasome activity increased in M1 cells, and to some extent under M2 conditions. Analyzing the polarization capability from LMP7 deficient mice revealed no effect on the LPS/IFNγ triggered M1 profile, but uncovered a distorted M2 profile for IL-4 stimulated LMP7-/- alveolar macrophages as characterized by increased M2 marker gene expression and CCL17 cytokine release. This shift in immunoproteasome-dependent M2 polarization was accompanied by amplified AKT/STAT6 activation and IRF4 expression in LMP7-/- alveolar macrophages. IL-13 stimulation of LMP7 deficient cells induced a similar M2 skewed profile and IL4Rα protein expression was generally elevated in LMP7-/- alveolar macrophages, indicating that amplified IL4R signaling in immunoproteasome defective cells may contribute to augmented M2 polarization. Importantly, treatment with an LMP7-specific proteasome inhibitor recapitulated the findings of genetic LMP7 inactivation. Our results thus suggest a novel role of immunoproteasome function for regulating innate immune function of macrophages by limiting IL4R expression and signaling.
2016-06-29 | GSE72000 | GEO
Project description:Increased plasma uric acid (hyperuricemia) has been associated with worse outcomes for chronic kidney disease (CKD). But some attempts to control uric acid (UA) in large-cohort clinical trials did not produce clinically meaningful benefits for CKD. Some studies suggest that only hyperuricemia with crystals, but not asymptomatic hyperuricemia promotes the progression of CKD. Salt-sensitivity (SS) in blood pressure is a prevalent trait that is sexually dimorphic and results in kidney damage. But the connection between hyperuricemia and SS hypertension (HTN) is still unclear. Here we tested the connection between the two using both male and female Dahl SS rats, a well-establish model of SS HTN. We hypothesized that mild asymptomatic hyperuricemia is beneficial in controlling the progression of SS HTN. A uricase inhibitor, oxonic acid (2%) (Oxo) was used to induce hyperuricemia and high-salt (HS) (4% NaCl) diet was used to induce SS HTN. After 3 weeks, in response to oxonic acid supplementation, both sexes showed a significant increase of UA in plasma compared to their respective HS-only controls (Males: 0.63 ±0.07 vs. 2.17 ±0.34; Females: 0.78 ±0.15 vs. 2.04 ±0.35 mg/dl, HS vs. HS/oxo). Interestingly, only male HS/oxo rats showed a significant increase in uricosuria (Males: 0.23 ±0.03 vs. 0.45 ±0.06; Femaels: 0.26 ±0.06 vs. 0.26 ±0.001 UA/Cre, HS vs. HS/oxo). Moreover, the mild hyperuricemia was associated with a significant attenuation of the progression and magnitude of the mean arterial pressure in male but not female rats (Males: 157 ±3 vs. 136 ±3; Females: 155 ±6 vs. 154 ±5 mmHg, HS vs. HS/oxo). Xanthine oxidase (XO) is one of the enzymes that produce UA, and its activity has been shown to affect HTN as well. Therefore, we examined the level of XO activity in the plasma after the treatment. While there was no difference in the activity based on the diet within each sex, females had significantly lower levels of XO activity compared to males in each of the diets. To further investigate the beneficial phenotype seen in male rats, we evaluate changes in the progression of renal pathology. The HS/oxo group compared to the HS group had a lower kidney weight/body weight ratio and lower protein cast accumulation, indicating lower kidney damage. Furthermore, the HS/Oxo treated males had less oxidative damage in their tubules than the HS-only males. Bulk-RNA seq done on the male kidneys revealed that attenuated HTN phenotype was associated with an increased expression in Mas1 (MAS receptor), Klk-1 (Kallikrein-1), and Pcsk6 (PCSK6 enzyme) which can all lead to the activation of different vasodilatory pathways. Our study showed that in male but not female Dahl SS rats, asymptomatic mild hyperuricemia accompanied by hyperuricosuria ameliorates the progression of SS HTN and protects kidneys from further damage. Thus, our findings challenge the notion of hyperuricemia being inherently detrimental to health and highlight that this is an oversimplified view of UA’s role in disease.
2024-07-10 | GSE269511 | GEO
Project description:Our team utilized single-cell RNA sequencing and spatial multi-omics to explore the spatial landscape of kidney in mice with hyperuricemia at single-cell level
2025-01-15 | GSE256431 | GEO
Project description:Our team utilized single-cell RNA sequencing and spatial multi-omics to explore the spatial landscape of kidney in mice with hyperuricemia at single-cell level
2025-01-22 | GSE258959 | GEO
Project description:GM-CSF paradoxically possesses ability to differentiate both classically activated macrophages (MØs) with dominant proinflammatory function (M1-like MØs) and alternative activated MØs with strong immunosuppressive function (M2-like MØs). The intrinsic regulatory mechanism responsible for functional polarization of MØs under GM-CSF signalling remains elusive. Here we revealed that cytokine-inducible SH2-containing protein (CIS), induced by GM-CSF, is a key determinant in controlling MØ polarization. Compared to WT MØs, Cish-/- MØs gained characteristics of alternative activated MØs (M2 MØs), showing high expression of prototypic M2 markers Arginase 1, Tgm2 and YM-1; strong suppression of T cell proliferation; and low production of IL-12 and other proinflammatory cytokines¬¬. Differing from canonical IL-4/STAT6/IRF4 signaling axis of M2 induction, development of M2 MØ characteristics in Cish-/- MØs was associated with intensified STAT5 activation and consequent IRF8 downregulation. Attenuation of GM-CSF signalling via JAK inhibition and IRF8 rescue corrected certain functional defects in Cish-/- MØs. As CIS inhibition in NK and T cells promotes anti-tumour immunity, we showed that CIS deficiency enhanced the development of intra-tumoural M2 MØs and reduced CTL induction within tumour microenvironment with elevated GM-CSF. Overall, we conclude that CIS acts as an intrinsic rheostat to control intense GM-CSF signalling in order to maintain proinflammatory functions of MØs. Targeting CIS as a checkpoint in cancer immunotherapy should consider its role in regulating myeloid cell function.
2023-01-21 | PXD018390 | Pride