bims-stacyt 2019-10-20 papers

Sci Rep. 2019 Oct 17. 9(1): 14931

Endoplasmic reticulum stress differentially modulates the IL-6 family of cytokines in murine astrocytes and macrophages.

Cristina L Sanchez, Savannah G Sims, John D Nowery, Gordon P Meares.

In many diseases, misfolded proteins accumulate within the endoplasmic reticulum (ER), leading to ER stress. In response, the cell initiates the unfolded protein response (UPR) to reestablish homeostasis. Additionally, in response to ER stress, various cell types mount an inflammatory response involving interleukin (IL)-6. While IL-6 has been widely studied, the impact of ER stress on other members of the IL-6 cytokine family, including oncostatin (OSM), IL-11, ciliary neurotrophic factor (CNTF), and leukemia inhibitor factor (LIF) remains to be elucidated. Here, we have examined the expression of the IL-6 family cytokines in response to pharmacologically-induced ER stress in astrocytes and macrophages, which express IL-6 in response to ER stress through different mechanisms. Our findings indicate that, in astrocytes, ER stress regulates mRNA expression of the IL-6 family of cytokines that is, in part, mediated by PKR-like ER kinase (PERK) and Janus kinase (JAK) 1. Additionally, in astrocytes, CNTF expression was suppressed through a PERK-dependent mechanism. Macrophages display a different profile of expression of the IL-6 family that is largely independent of PERK. However, IL-6 expression in macrophages was dependent on JAK signaling. Overall, this study demonstrates the cell-specific and differential mechanisms controlling expression of the IL-6 family of cytokines in response to ER stress.

DOI: https://doi.org/10.1038/s41598-019-51481-6

Int J Mol Sci. 2019 Oct 12. pii: E5065. [Epub ahead of print]20(20):

Hypoxia Induced Heparan Sulfate Primes the Extracellular Matrix for Endothelial Cell Recruitment by Facilitating VEGF-Fibronectin Interactions.

Jo Ann Buczek-Thomas, Celeste B Rich, Matthew A Nugent.

Vascular endothelial growth factor-A (VEGF) is critical for the development, growth, and survival of blood vessels. Retinal pigmented epithelial (RPE) cells are a major source of VEGF in the retina, with evidence that the extracellular matrix (ECM)-binding forms are particularly important. VEGF associates with fibronectin in the ECM to mediate distinct signals in endothelial cells that are required for full angiogenic activity. Hypoxia stimulates VEGF expression and angiogenesis; however, little is known about whether hypoxia also affects VEGF deposition within the ECM. Therefore, we investigated the role of hypoxia in modulating VEGF-ECM interactions using a primary retinal cell culture model. We found that retinal endothelial cell attachment to RPE cell layers was enhanced in cells maintained under hypoxic conditions. Furthermore, we found that agents that disrupt VEGF-fibronectin interactions inhibited endothelial cell attachment to RPE cells. We also found that hypoxia induced a general change in the chemical structure of the HS produced by the RPE cells, which correlated to changes in the deposition of VEGF in the ECM, and we further identified preferential binding of VEGFR2 over VEGFR1 to VEGF laden-fibronectin matrices. Collectively, these results indicate that hypoxia-induced HS may prime fibronectin for VEGF deposition and endothelial cell recruitment by promoting VEGF-VEGFR2 interactions as a potential means to control angiogenesis in the retina and other tissues.

Keywords: age-related macular degeneration; angiogenesis; endothelial cell; fibronectin; hypoxia; retina; vascular endothelial growth factor

DOI: https://doi.org/10.3390/ijms20205065

J Clin Endocrinol Metab. 2019 Oct 13. pii: dgz090. [Epub ahead of print]

A role for Oncostatin M in the impairment of glucose homeostasis in obesity.

OBJECTIVE: The aim of this study was to evaluate the relationship of OSM with the inflammatory state that leads to impaired glucose homeostasis in obesity. We also assessed whether OSM immunoneutralization could revert metabolic disturbances caused by a high-fat diet (HFD) in mice.DESIGN: 28 patients with severe obesity were included and stratified into two groups: 1) glucose levels < 100 mg/dL and 2) glucose levels > 100 mg/dL. White adipose tissue was obtained to examine OSM gene expression. Human adipocytes were used to evaluate the effect of OSM in the inflammatory response, and HFD-fed C57BL/6J mice were injected with anti-OSM antibody to evaluate its effects.
RESULTS: OSM expression was elevated in subcutaneous and visceral fat from patients with obesity and hyperglycemia, and correlated with Glut4 mRNA levels, serum insulin, HOMA-IR, and inflammatory markers. OSM inhibited adipogenesis and induced inflammation in human adipocytes. Finally, OSM receptor knockout mice had increased Glut4 mRNA levels in adipose tissue, and OSM immunoneutralization resulted in a reduction of glucose levels and Ccl2 expression in adipose tissue from HFD-fed mice.
CONCLUSIONS: OSM contributes to the inflammatory state during obesity and may be involved in the development of insulin resistance.

Keywords: Oncostatin M; inflammation; insulin resistance; obesity

DOI: https://doi.org/10.1210/clinem/dgz090

J Clin Invest. 2019 Oct 15. pii: 127515. [Epub ahead of print]

Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy.

Nikita S Sharma, Vineet K Gupta, Vanessa T Garrido, Roey Hadad, Brittany C Durden, Kousik Kesh, Bhuwan Giri, Anthony Ferrantella, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee.

Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA4, PD1, PDL1) has not been very successful against PDAC. The robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that is rich in hyaluronan, plays an integral role in this immune evasion. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on one hand and influence the hyaluronan synthesis in the ECM on the other. The rate-limiting enzyme of the pathway, glutamine-fructose amidotransferase (GFAT1), uses glutamine and fructose 6-phosphate to eventually synthesize UDP-GlcNAc. In the current manuscript, we targeted this glutamine-utilizing enzyme by a small molecule glutamine analog (6-diazo-5-oxo-L-norleucine or DON). Our results showed that DON decreased the self-renewal potential and metastatic ability of tumor cell. Further, treatment with DON decreased hyaluronan and collagen in the tumor microenvironment, leading to an extensive remodeling of the ECM, and an increased infiltration CD8+ T-cells. Additionally, treatment with DON sensitized pancreatic tumors to anti-PD1 therapy resulting in tumor regression and prolonged survival.

Keywords: Cancer immunotherapy; Extracellular matrix; Oncology

DOI: https://doi.org/10.1172/JCI127515