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PPARγ induces PD-L1 expression in MSS+ colorectal cancer cells
Only a small subset of colorectal cancer (CRC) patients benefits from immunotherapies, comprising blocking antibodies (Abs) against checkpoint receptor “programmed-cell-death-1” (PD1) and its ligand (PD-L1), because most cases lack the required mutational burden and neo-antigen load caused by microsatellite instability (MSI) and/or an inflamed, immune cell-infiltrated PD-L1+ tumor microenvironment.
Peroxisome proliferator-activated-receptor-gamma (PPARγ), a metabolic transcription factor stimulated by anti-diabetic drugs, has been previously implicated in pre/clinical responses to immunotherapy. We therefore raised the hypothesis that PPARγ induces PD-L1 on microsatellite stable (MSS) tumor cells to enhance Ab-target engagement and responsiveness to PD-L1 blockage.
We found that PPARγ-agonists upregulate PD-L1 mRNA/protein expression in human gastrointestinal cancer cell lines and MSS+ patient-derived tumor organoids (PDOs). Mechanistically, PPARγ bound to and activated DNA-motifs similar to cognate PPARγ-responsive-elements (PPREs) in the proximal -2 kb promoter of the human PD-L1 gene.
PPARγ-agonist reduced proliferation and viability of tumor cells in co-cultures with PD-L1 blocking Ab and lymphokine-activated killer cells (LAK) derived from the peripheral blood of CRC patients or healthy donors. Thus, metabolic modifiers improved the antitumoral response of immune checkpoint Ab, proposing novel therapeutic strategies for CRC.
Increased Expression of PPAR–γ Modulates Monocytes Into a M2-Like Phenotype in SLE Patients: An Implicative Protective Mechanism and Potential Therapeutic Strategy of Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is a spectrum of autoimmune disorders characterized by continuous inflammation and the production of autoantibodies. Monocytes, as precursors of dendritic cells and macrophages, are involved in the pathogenesis of SLE, particularly in the inflammatory reactions. Previous studies have proved that Pam3CSK4, as a synthetic ligand of TLR2, could stimulate monocytes to differentiated into a M2-like phenotype which presented immunosuppressive functions.
However, the underlying mechanisms remain to be further studied. Here, we reported an increased expression of PPAR–γ in the CD14+ monocytes from SLE patients, particularly in the treated group of SLE patients and the group with positive anti-dsDNA antibodies.
Additionally, PPAR–γ expression decreased in the SLE patients with skin lesion. Furthermore, we demonstrated that Pam3CSK4 stimulation can decrease the expression of CCR7, CD80, IL-1β, IL-6, IL-12, and NF-κB which were related to the M1-like subset of monocytes and increased the expression of ARG1 which was related to the M2-like subset through upregulated PPAR–γ expression and consequently downregulated NF-κB expression in the CD14+ monocytes in a time-dependent manner.
ChIP-qPCR results further demonstrated that Pam3CSK4 pretreatment could modulate PPAR–γ expression by regulating histone modification through the inhibition of Sirt1 binding to the PPAR–γ promoter. Taken together, our study indicated a protective role of TLR2/Sirt1/PPAR–γ pathway in the pathogenesis of SLE which provided potential therapeutic strategies.
Natural polymorphism of Ym1 regulates pneumonitis through alternative activation of macrophages
We have positionally cloned the Ym1 gene, with a duplication and a promoter polymorphism, as a major regulator of inflammation. Mice with the RIIIS/J haplotype, with the absence of Ym1 expression, showed reduced susceptibility to mannan-enhanced collagen antibody-induced arthritis and to chronic arthritis induced by intranasal exposure of mannan.
Depletion of lung macrophages alleviated arthritis, whereas intranasal supplement of Ym1 protein to Ym1-deficient mice reversed the disease, suggesting a key role of Ym1 for inflammatory activity by lung macrophages. Ym1-deficient mice with pneumonitis had less eosinophil infiltration, reduced production of type II cytokines and IgG1, and skewing of macrophages toward alternative activation due to enhanced STAT6 activation. Proteomics analysis connected Ym1 polymorphism with changed lipid metabolism.
Induced PPAR–γ and lipid metabolism in Ym1-deficient macrophages contributed to cellular polarization. In conclusion, the natural polymorphism of Ym1 regulates alternative activation of macrophages associated with pulmonary inflammation.
Dietary Gluten and Neurodegeneration: A Case for Preclinical Studies
Although celiac disease (CD) is an autoimmune disease that primarily involves the intestinal tract, mounting evidence suggests that a sizeable number of patients exhibit neurological deficits. About 40% of the celiac patients with neurological manifestations have circulating antibodies against neural tissue transglutaminase-6 (tTG6). While early diagnosis and strict adherence to a gluten-free diet (GFD) have been recommended to prevent neurological dysfunction, better therapeutic strategies are needed to improve the overall quality of life.
Dysregulation of the microbiota-gut-brain axis, presence of anti-tTG6 antibodies, and epigenetic mechanisms have been implicated in the pathogenesis. It is also possible that circulating or gut-derived extracellular structures and including biomolecular condensates and extracellular vesicles contribute to disease pathogenesis.
There are several avenues for shaping the dysregulated gut homeostasis in individuals with CD, non-celiac gluten sensitivity (NCGS) and/or neurodegeneration. In addition to GFD and probiotics, nutraceuticals, such as phyto and synthetic cannabinoids, represent a new approach that could shape the host microbiome towards better prognostic outcomes.
Finally, we provide a data-driven rationale for potential future pre-clinical research involving non-human primates (NHPs) to investigate the effect of nutraceuticals, such as phyto and synthetic cannabinoids, either alone or in combination with GFD to prevent/mitigate dietary gluten-induced neurodegeneration.
β-Caryophyllene Mitigates Collagen Antibody Induced Arthritis (CAIA) in Mice Through a Cross-Talk between CB2 and PPAR–γ Receptors.
β-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist that tempers inflammation. An interaction between the CB2 receptor and peroxisome proliferator-activated receptor gamma (PPAR–γ) has been suggested and PPAR–γ activation exerts anti-arthritic effects. The aim of this study was to characterize the therapeutic activity of BCP and to investigate PPAR–γ involvement in a collagen antibody induced arthritis (CAIA) experimental model.
CAIA was induced through intraperitoneal injection of a monoclonal antibody cocktail and lipopolysaccharide (LPS; 50 μg/100 μL/ip). CAIA animals were then randomized to orally receive either BCP (10 mg/kg/100 μL) or its vehicle (100 μL of corn oil). BCP significantly hampered the severity of the disease, reduced relevant pro-inflammatory cytokines, and increased the anti-inflammatory cytokine IL-13.
BCP also decreased joint expression of matrix metalloproteinases 3 and 9. Arthritic joints showed increased COX2 and NF-ĸB mRNA expression and reduced expression of the PPARγ coactivator-1 alpha, PGC-1α, and PPAR–γ. These conditions were reverted following BCP treatment. Finally, BCP reduced NF-ĸB activation and increased PGC-1α and PPAR–γ expression in human articular chondrocytes stimulated with LPS.
PPAR gamma antibody |
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| 70R-12105 | Fitzgerald | 100 ug | EUR 343 |
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Description: Rabbit polyclonal PPAR gamma antibody |
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PPAR gamma antibody |
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| 70R-35496 | Fitzgerald | 100 ug | EUR 294 |
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Description: Purified Rabbit polyclonal PPAR gamma antibody |
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PPAR gamma Antibody |
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| AF6284 | Affbiotech | 200ul | EUR 420 |
PPAR gamma Antibody |
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| AF6284-100ul | Affinity Biosciences | 100ul | EUR 280 |
PPAR gamma Antibody |
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| AF6284-200ul | Affinity Biosciences | 200ul | EUR 350 |
PPAR gamma Antibody |
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| AF6675 | Affbiotech | 100ul | EUR 420 |
PPAR gamma Antibody |
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| AF6675-100ul | Affinity Biosciences | 100ul | EUR 280 |
PPAR gamma Antibody |
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| AF6675-200ul | Affinity Biosciences | 200ul | EUR 350 |
PPAR- gamma Antibody |
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| ABF6284 | Nova Lifetech | 100ug | EUR 325 |
PPAR Gamma Antibody |
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| GWB-5CA2DA | GenWay Biotech | 0.05 mg | Ask for price |
PPAR Gamma Antibody |
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| GWB-2253AA | GenWay Biotech | 0.05 mg | Ask for price |
PPAR gamma Antibody |
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| R30380 | NSJ Bioreagents | 100 ug | EUR 356.15 |
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Description: The peroxisome proliferator-activated receptors are a group of three nuclear receptor isoforms, PPAR gamma, alpha, delta, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPAR gamma is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes. Isoforms 1 and 2 result from alternative splicing and have ligand-dependent and -independent activation domains. PPAR gamma is a member of a family of nuclear receptors/ligand-dependent transcription factors, which bind to hormone response elements on target gene promoters. Ameshima et al.(2003) found that it is abundantly expressed in normal lung tissues, especially in endothelial cells, but that its expression is reduced or absent in the angiogenic plexiform lesions of pulmonary hypertensive lungs and in the vascular lesions of a rat model of severe pulmonary hypertension. And they conclude that fluid shear stress decreases its expression in endothelial cells and that loss of expression characterizes an abnormal, proliferating, apoptosis-resistant endothelial cell phenotype. |
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PPAR gamma Antibody |
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| MBS8582696-01mL | MyBiosource | 0.1mL | EUR 305 |
PPAR gamma Antibody |
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| MBS8582696-01mLAF405L | MyBiosource | 0.1mL(AF405L) | EUR 465 |
PPAR gamma Antibody |
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| MBS8582696-01mLAF405S | MyBiosource | 0.1mL(AF405S) | EUR 465 |
PPAR gamma Antibody |
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| MBS8582696-01mLAF610 | MyBiosource | 0.1mL(AF610) | EUR 465 |
PPAR gamma Antibody |
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| MBS8582696-01mLAF635 | MyBiosource | 0.1mL(AF635) | EUR 465 |
These effects were reverted by AM630, a CB2 receptor antagonist. These results suggest that BCP ameliorates arthritis through a cross-talk between CB2 and PPAR–γ.
