An inflammatory triangle in Sarcoidosis: PPAR-γ, immune microenvironment, and inflammation

Jabbari, Parnia; Sadeghalvad, Mona; Rezaei, Nima

doi:10.1080/14712598.2021.1913118

Cited by 17 publications

(14 citation statements)

References 76 publications

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“…Alveolar macrophages present the specific antigenic peptides in association with human leukocyte antigen molecules to specific T cells (38). In addition to the alveolar macrophages which play a critical role in granuloma formation, increased activation of T cells, NK cells and mast cells could promote this process as well (39). The cytokine IL-33 ameliorates the regulatory effects of T cells in the occurrence of pulmonary SA.…”

Section: Discussionmentioning

confidence: 99%

BATF2 and PDK4 as diagnostic molecular markers of sarcoidosis and their relationship with immune infiltration

He¹,

Li²,

Zhou³

et al. 2022

Ann Transl Med

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Background: Sarcoidosis (SA) is an immune disorder disease featuring granulomas formation with a controversial etiopathogenesis. We aimed to uncover potential markers for SA diagnosis and explore how immune cell infiltration contributes to the pathogenesis of SA.Methods: Sarcoidosis GSE83456 samples and GSE42834 from Gene Expression Omnibus (GEO) were analyzed as the training and external validation sets, respectively. Firstly, R statistical software was employed to uncover the differentially expressed genes (DEGs) of GSE83456. Weighted gene co-expression network analysis (WGCNA) was used to reveal the key module of DEGs. Secondly, the genes of the key module were used to analyze functional correlations. Thirdly, support vector machine (SVM) algorithms and least absolute shrinkage and selection operator (LASSO) logistic regression were applied for screening and verification of the diagnostic markers for key module genes. Finally, the infiltration of immune cells in SA patients' blood samples was assessed by Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), after which correlations of diagnostic markers immune cell and infiltration were explored. Serum samples collected from human research participants were used for confirmatory analysis of bioinformatics. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of BATF2 and PDK4.Results: In total, 580 DEGs were identified from the key module. The genes PDK4 [area under the curve (AUC) =0.942] and BATF4 (AUC =0.980) were revealed as diagnostic markers of SAs. The diagnostic power of the 2 genes was verified in GSE42834. We found that monocytes, T cells regulatory (Tregs), mast cells, macrophages, natural killer (NK) cells, and dendritic cells (DC) may contribute to SA development through immune cell infiltration study. In addition, PDK4 and BATF4 were closely associated with these immune cells.Both BATF2 and PDK4 were highly expressed in active pulmonary SA. Using non-SA patients as controls, the AUC of serum PDK4, BATF2, and their combination for the diagnosis of active pulmonary SA was 0.798 (95% CI: 0.701 to 0.876), 0.895 (95% CI: 0.813 to 0.950), and 0.910 (95% CI: 0.831 to 0.960), respectively. Conclusions:The genes PDK4 and BATF4 could be used as diagnostic markers of active pulmonary SA.Immune cell infiltration severs an important role in SA.

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Section: Discussionmentioning

confidence: 99%

BATF2 and PDK4 as diagnostic molecular markers of sarcoidosis and their relationship with immune infiltration

He¹,

Li²,

Zhou³

et al. 2022

Ann Transl Med

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“…Moreover, numerous studies have shown that hyperglycemia causes severe inflammation [ 86 , 87 ]. Researchers have outlined thiazolidinediones, especially pioglitazone and rosiglitazone, to manage endothelial problems [ 95 ]. Treatment with a PPARƳ agonist inhibits LPS-induced endothelial inflammation by reducing IL-6, VCAM, TNF-α, and mRNA expression [ 96 ].…”

Section: Discussionmentioning

confidence: 99%

Partial Synthetic PPARƳ Derivative Ameliorates Aorta Injury in Experimental Diabetic Rats Mediated by Activation of miR-126-5p Pi3k/AKT/PDK 1/mTOR Expression

et al. 2022

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Type 2 diabetes mellitus (T2D) is a world wild health care issue marked by insulin resistance, a risk factor for the metabolic disorder that exaggerates endothelial dysfunction, increasing the risk of cardiovascular complications. Peroxisome proliferator-activated receptor PPAR) agonists have therapeutically mitigated hyperlipidemia and hyperglycemia in T2D patients. Therefore, we aimed to experimentally investigate the efficacy of newly designed synthetic PPARα/Ƴ partial agonists on a High-Fat Diet (HFD)/streptozotocin (STZ)-induced T2D. Female Wistar rats (200 ± 25 g body weight) were divided into four groups. The experimental groups were fed the HFD for three consecutive weeks before STZ injection (45 mg/kg/i.p) to induce T2D. Standard reference PPARƳ agonist pioglitazone and the partial synthetic PPARƳ (PIO; 20 mg/kg/BW, orally) were administered orally for 2 weeks after 72 h of STZ injection. The aorta tissue was isolated for biological ELISA, qRT-PCR, and Western blotting investigations for vascular inflammatory endothelial mediators endothelin-1 (ET-1), intracellular adhesion molecule 1 (ICAM-1), E-selectin, and anti-inflammatory vasoactive intestinal polypeptide (VIP), as well as microRNA126-5p and p-AKT/p-Pi3k/p-PDK-1/p-mTOR, endothelial Nitric Oxide Synthase (eNOS) immunohistochemical staining all are coupled with and histopathological examination. Our results revealed that HFD/STZ-induced T2D increased fasting blood glucose, ET-1, ICAM-1, E-selectin, and VIP levels, while decreasing the expression of both microRNA126-5p and p-AKT/p-Pi3k/p-PDK-1/p-mTOR phosphorylation. In contrast, the partial synthetic PPARƳ derivative evidenced a vascular alteration significantly more than reference PIO via decreasing (ET-1), ICAM-1, E-selectin, and VIP, along with increased expression of microRNA126-5p and p-AKT/p-Pi3k/p-PDK-1/p-mTOR. In conclusion, the partial synthetic PPARƳ derivative significantly affected HFD/STZ-induced T2D with vascular complications in the rat aorta.

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“…Further studies attempting to elucidate this pathogenesis have found increased mTORc1 (mechanistic target of rapamycin complex 1) signal transduction [38 ▪▪ ] as well as increased Janus kinase-signal transducer and activation of transcription (JAK-STAT) activity in sarcoidosis [39 ▪▪ ]. Alveolar macrophages from sarcoid patients have shown reduced levels and activity of peroxisome proliferator-activated receptor (PPAR) and are hypothesized to contribute to the inflammatory milieu suitable for granuloma formation [40 ▪▪ ].…”

Section: Sarcoidosis As An Autoimmune Diseasementioning

confidence: 99%

“…In contrast to how advancements in molecular and genetic analysis have provided new evidence supporting infectious triggers and genetic susceptibility, advancements in immunology have disproven the long held Th1 paradigm of sarcoidosis and replaced it with a more comprehensive model of T-cell plasticity and cytokine signaling pathways [37,38 ▪▪ –40 ▪▪ ].…”

Section: Sarcoidosis As An Autoimmune Diseasementioning

confidence: 99%

Sarcoidosis and autoimmunity

Song¹,

Manansala²,

Parmar

et al. 2021

Current Opinion in Pulmonary Medicine

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Purpose of reviewSarcoidosis is a poorly understood multisystem granulomatous disease that frequently involves the lungs but can affect any organ system. In this review, we summarize recent developments in the understanding of the immune dysregulation seen in sarcoidosis and propose a new expanded definition of human autoimmunity in sarcoidosis, and the implications it would have on treating sarcoidosis with targeted immunotherapy regimens in the future. Recent findingsSarcoidosis has been linked to infectious organisms like Mycobacterium and Cutibacterium, and certain manifestations of sarcoidosis have been linked to specific HLA alleles, but the overall pathogenesis remains uncertain. Sarcoidosis patients have similar patterns of cellular immune dysregulation seen in other autoimmune diseases like rheumatoid arthritis, and recent large-scale population studies show that sarcoidosis frequently presents with other autoimmune diseases. SummaryAdvancements in the understanding of sarcoidosis support its consideration as an autoimmune disease. Sarcoidosis patients carry a higher risk of comorbid autoimmune conditions which offers an excellent opportunity to further understand autoimmunity and explore biologic therapies in sarcoidosis treatment, and furthermore will better targeted immunotherapy regimens for sarcoidosis patients in the future.

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An inflammatory triangle in Sarcoidosis: PPAR-γ, immune microenvironment, and inflammation

Cited by 17 publications

References 76 publications

BATF2 and PDK4 as diagnostic molecular markers of sarcoidosis and their relationship with immune infiltration

BATF2 and PDK4 as diagnostic molecular markers of sarcoidosis and their relationship with immune infiltration

Partial Synthetic PPARƳ Derivative Ameliorates Aorta Injury in Experimental Diabetic Rats Mediated by Activation of miR-126-5p Pi3k/AKT/PDK 1/mTOR Expression

Sarcoidosis and autoimmunity

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