bims-stacyt 2020-08-30 papers

Cell Metab. 2020 Aug 19. pii: S1550-4131(20)30415-0. [Epub ahead of print]

The Role of HIF in Immunity and Inflammation.

HIF is a transcription factor that plays an essential role in the cellular response to low oxygen, orchestrating a metabolic switch that allows cells to survive in this environment. In immunity, infected and inflamed tissues are often hypoxic, and HIF helps immune cells adapt. HIF-α stabilization can also occur under normoxia during immunity and inflammation, where it regulates metabolism but in addition can directly regulate expression of immune genes. Here we review the role of HIF in immunity, including its role in macrophages, dendritic cells, neutrophils, T cells, and B cells. Its role in immunity is as essential for cellular responses as it is in its original role in hypoxia, with HIF being implicated in multiple inflammatory diseases and in immunosuppression in tumors.

DOI: https://doi.org/10.1016/j.cmet.2020.08.002

Cells. 2020 Aug 23. pii: E1948. [Epub ahead of print]9(9):

Loganin Attenuates High Glucose-Induced Schwann Cells Pyroptosis by Inhibiting ROS Generation and NLRP3 Inflammasome Activation.

Yu-Chi Cheng, Li-Wen Chu, Jun-Yih Chen, Su-Ling Hsieh, Yu-Chin Chang, Zen-Kong Dai, Bin-Nan Wu.

Diabetic peripheral neuropathy (DPN) is caused by hyperglycemia, which induces oxidative stress and inflammatory responses that damage nerve tissue. Excessive generation of reactive oxygen species (ROS) and NOD-like receptor protein 3 (NLRP3) inflammasome activation trigger the inflammation and pyroptosis in diabetes. Schwann cell dysfunction further promotes DPN progression. Loganin has been shown to have antioxidant and anti-inflammatory neuroprotective activities. This study evaluated the neuroprotective effect of loganin on high-glucose (25 mM)-induced rat Schwann cell line RSC96 injury, a recognized in vitro cell model of DPN. RSC96 cells were pretreated with loganin (0.1, 1, 10, 25, 50 μM) before exposure to high glucose. Loganin's effects were examined by CCK-8 assay, ROS assay, cell death assay, immunofluorescence staining, quantitative RT-PCR and western blot. High-glucose-treated RSC96 cells sustained cell viability loss, ROS generation, NF-κB nuclear translocation, P2 × 7 purinergic receptor and TXNIP (thioredoxin-interacting protein) expression, NLRP3 inflammasome (NLRP3, ASC, caspase-1) activation, IL-1β and IL-18 maturation and gasdermin D cleavage. Those effects were reduced by loganin pretreatment. In conclusion, we found that loganin's antioxidant effects prevent RSC96 Schwann cell pyroptosis by inhibiting ROS generation and suppressing NLRP3 inflammasome activation.

Keywords: NLRP3 inflammasome; Schwann cell; high glucose; loganin; pyroptosis; reactive oxygen species

DOI: https://doi.org/10.3390/cells9091948

Front Endocrinol (Lausanne). 2020 ;11 445

The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes.

Yen-Hsiang Chang, Hung-Yu Lin, Feng-Chih Shen, Yu-Jih Su, Jiin-Haur Chuang, Tsu-Kung Lin, Chia-Wei Liou, Ching-Yi Lin, Shao-Wen Weng, Pei-Wen Wang.

Background: Plenty of evidence suggested that chronic low-grade inflammation triggered by innate immunity activation contributes to the pathogenesis of type 2 diabetes (T2D). Using the trans-mitochondrial cybrid cell model, we have demonstrated that mitochondria independently take part in the pathological process of insulin resistance (IR) and pro-inflammatory phenotype in cybrid cells harboring mitochondrial haplogroup B4, which are more likely to develop T2D. The mitochondrial network is more fragmented, and the expression of fusion-related proteins is low in Cybrid B4. We also discovered the causal role of mitochondrial dynamics (mtDYN) proteins in regulating IR in this cybrid model, and the bidirectional interaction between mtDYN and mitochondrial oxidative stress is considered etiologically important. In this study, we further investigated whether mtDYN bridges the gap between nutrient excess and chronic inflammation in T2D. Methods: Trans-mitochondrial cybrid cells derived from the 143B human osteosarcoma cell line were cultured in a medium containing glucose (25 mM) with or without saturated fatty acid (0.25 mM BSA-conjugated palmitate), and the expression of innate immunity/inflammasome molecules was compared between cybrid B4 (the major T2D-susceptible haplogroup among the Chinese population) and cybrid D4 (the major T2D-resistant haplogroup among the Chinese population). We investigated the causal relationship between mtDYN and nutrient excess-induced inflammation in cybrid B4 by genetic manipulation of mtDYN and by pharmacologically inhibiting mitochondrial fission using the Drp1 inhibitor, mdivi-1, and metformin. Results: Under nutrient excess with high fatty acid, cybrid B4 presented increased mitochondrial pro-fission profiles and enhanced chronic inflammation markers (RIG-I, MDA5, MAVS) and inflammasome (NLRP3, Caspase-1, IL-1β), whereas the levels in cybrid D4 were not or less significantly altered. In cybrid B4 under nutrient excess, overexpression of fusion proteins (Mfn1 or Mfn2) significantly repressed the expression of innate immunity/inflammasome-related molecules, while knockdown had a less significant effect. On the contrary, knockdown of fission proteins (Drp1 or Fis1) significantly repressed the expression of innate immunity/inflammasome-related molecules, while overexpression had a less significant effect. In addition, Drp1 inhibitor mdivi-1 and metformin inhibited mitochondrial fission and attenuated the pro-inflammation expression as well. Conclusion: Our results discovered the causal relationship between mtDYN and nutrient excess-induced chronic inflammation in a diabetes-susceptible cell model. Targeting mtDYN by direct interfering pro-fission can be a therapeutic intervention for chronic inflammation in T2D.

Keywords: inflammation; innate immunity; mitochondrial dynamics; nutrient excess; type 2 diabetes

DOI: https://doi.org/10.3389/fendo.2020.00445

Sleep Breath. 2020 Aug 25.

Intermittent hypoxia induces tumor immune escape in murine S180 solid tumors via the upregulation of TGF-β1 in mice.

Lijuan Ma, Weibi Shan, Xinguo Ding, Pan Yang, Azmat Rozjan, Qiaoling Yao.

PURPOSE: Studies have shown that intermittent hypoxia (IH) alters host immune functions and promotes tumor growth. However, the relevant mechanisms of these effects have not been completely elucidated. We hypothesized that IH promotes the growth of tumors by changing cytokine levels in the tumor microenvironment and inducing immune escape.METHODS: Sarcoma-180 (S180) solid tumor cells were injected into the right flank of Kunming mice. The mice were then randomly divided into the IH and room air (RA) groups. The mice were euthanized 2 weeks after IH exposure, and the weight of tumor tissues was measured. Next, IL-6, IL-17, IL-10, and TNF-α levels in tumor tissues were measured via enzyme linked immunosorbent assay (ELISA), and hypoxia inducible factor-1α (HIF-1α) and transforming growth factor β1 (TGF-β1) expressions were examined through Western blot analysis.
RESULTS: Two weeks of IH exposure significantly accelerated the growth of S180 solid tumors. Western blot analysis results showed that the expression levels of HIF-1α and TGF-β1 in S180 tumors in the IH group were significantly upregulated compared with those in the RA group. ELISA results showed that compared with the RA group, the IH group had significantly increased TNF-α and IL-10 (P < 0.05) and significantly decreased IL-17 (P < 0.05).
CONCLUSION: IH might promote the growth of S180 solid tumors by inhibiting the antitumor immune response and inducing tumor immune escape via the upregulation of TGF-β1.

Keywords: Immune escape; Intermittent hypoxia; S180 solid tumor; TGF-β1

DOI: https://doi.org/10.1007/s11325-020-02166-2

Nat Rev Immunol. 2020 Aug 24.

Lactate modulation of immune responses in inflammatory versus tumour microenvironments.

Michelangelo Certo, Chin-Hsien Tsai, Valentina Pucino, Ping-Chih Ho, Claudio Mauro.

The microenvironment in cancerous tissues is immunosuppressive and pro-tumorigenic, whereas the microenvironment of tissues affected by chronic inflammatory disease is pro-inflammatory and anti-resolution. Despite these opposing immunological states, the metabolic states in the tissue microenvironments of cancer and inflammatory diseases are similar: both are hypoxic, show elevated levels of lactate and other metabolic by-products and have low levels of nutrients. In this Review, we describe how the bioavailability of lactate differs in the microenvironments of tumours and inflammatory diseases compared with normal tissues, thus contributing to the establishment of specific immunological states in disease. A clear understanding of the metabolic signature of tumours and inflammatory diseases will enable therapeutic intervention aimed at resetting the bioavailability of metabolites and correcting the dysregulated immunological state, triggering beneficial cytotoxic, inflammatory responses in tumours and immunosuppressive responses in chronic inflammation.

DOI: https://doi.org/10.1038/s41577-020-0406-2

Front Endocrinol (Lausanne). 2020 ;11 479

Cytokine Output of Adipocyte-iNKT Cell Interplay Is Skewed by a Lipid-Rich Microenvironment.

Robert J van Eijkeren, Imogen Morris, Anouska Borgman, Angela Markovska, Eric Kalkhoven.

The complex direct and indirect interplay between adipocytes and various adipose tissue (AT)-resident immune cells plays an important role in maintaining local and whole-body insulin sensitivity. Adipocytes can directly interact with and activate AT-resident invariant natural killer T (iNKT) cells through CD1d-dependent presentation of lipid antigens, which is associated with anti-inflammatory cytokine production in lean AT (IL-4, IL-10). Whether alterations in the microenvironment, i.e., increased free fatty acids concentrations or altered cytokine/adipokine profiles as observed in obesity, directly affect adipocyte-iNKT cell communication and subsequent cytokine output is currently unknown. Here we show that the cytokine output of adipocyte-iNKT cell interplay is skewed by a lipid-rich microenvironment. Incubation of mature 3T3-L1 adipocytes with a mixture of saturated and unsaturated fatty acids specifically reduced insulin sensitivity and increased lipolysis. Reduced activation of the CD1d-invariant T-Cell Receptor (TCR) signaling axis was observed in Jurkat reporter cells expressing the invariant NKT TCR, while co-culture assays with a iNKT hybridoma cell line (DN32.D3) skewed the cytokine output toward reduced IL-4 secretion and increased IFNγ secretion. Importantly, co-culture assays of mature 3T3-L1 adipocytes with primary iNKT cells isolated from visceral AT showed a similar shift in cytokine output. Collectively, these data indicate that iNKT cells display considerable plasticity with respect to their cytokine output, which can be skewed toward a more pro-inflammatory profile in vitro by microenvironmental factors like fatty acids.

Keywords: CD1d; adipocytes; iNKT cell; insulin resistance; lipolysis

DOI: https://doi.org/10.3389/fendo.2020.00479