bims-stacyt 2020-11-22 papers

Nat Rev Cancer. 2020 Nov 19.

Endoplasmic reticulum stress signals in the tumour and its microenvironment.

Protein handling, modification and folding in the endoplasmic reticulum (ER) are tightly regulated processes that determine cell function, fate and survival. In several tumour types, diverse oncogenic, transcriptional and metabolic abnormalities cooperate to generate hostile microenvironments that disrupt ER homeostasis in malignant and stromal cells, as well as infiltrating leukocytes. These changes provoke a state of persistent ER stress that has been demonstrated to govern multiple pro-tumoural attributes in the cancer cell while dynamically reprogramming the function of innate and adaptive immune cells. Aberrant activation of ER stress sensors and their downstream signalling pathways have therefore emerged as key regulators of tumour growth and metastasis as well as response to chemotherapy, targeted therapies and immunotherapy. In this Review, we discuss the physiological inducers of ER stress in the tumour milieu, the interplay between oncogenic signalling and ER stress response pathways in the cancer cell and the profound immunomodulatory effects of sustained ER stress responses in tumours.

DOI: https://doi.org/10.1038/s41568-020-00312-2

Bioessays. 2020 Nov 16. e2000067

How immune-cell fate and function are determined by metabolic pathway choice: The bioenergetics underlying the immune response.

Marcela Hortová-Kohoutková, Petra Lázničková, Jan Frič.

Immune cells are highly dynamic in their response to the tissue environment. Most immune cells rapidly change their metabolic profile to obtain sufficient energy to engage in defensive or homeostatic processes. Such "immunometabolism" is governed through intermediate metabolites, and has a vital role in regulating immune-cell function. The underlying metabolic reactions are shaped by the abundance and accessibility of specific nutrients, as well as the overall metabolic status of the host. Here, we discuss how different immune-cell types gain a sufficient energy supply. We then explain how immune cells perform various functions under challenged conditions and expend energy to sustain homeostasis. Finally, we speculate on how the immune-cell metabolic profile might be modulated in health and disease, by manipulating nutrient availability. By such intervention, the recovery of patient with dysregulated immune system responses might be sped up and the fitness of an individual efficiently restored.

Keywords: energy demand; immune-cell polarization; immunometabolism; nutrient availability

DOI: https://doi.org/10.1002/bies.202000067

Arch Biochem Biophys. 2020 Nov 11. pii: S0003-9861(20)30677-9. [Epub ahead of print]696 108668

Mitochondrial stress and GDF15 in the pathophysiology of sepsis.

Yasunori Fujita, Masafumi Ito, Ikuroh Ohsawa.

Mitochondria are multifunctional organelles that regulate diverse cellular processes. Mitochondrial stress, including stress generated by electron transport chain defects and impaired mitochondrial proteostasis, is intimately involved in various diseases and pathological conditions. Sepsis is a life-threatening condition that occurs when an imbalanced host response to infection leads to organ dysfunction. Metabolic disturbances and impaired immune responses are implicated in the pathogenesis and development of sepsis. Given that mitochondria play central roles in cellular metabolism, mitochondrial stress is predicted to be involved in the pathological mechanism of sepsis. Under mitochondrial stress, cells activate stress response systems to maintain homeostasis. This mitochondrial stress response transcriptionally activates genes involved in cell survival and death. Mitochondrial stress also induces the release of distinctive secretory proteins from cells. Recently, we showed that growth differentiation factor 15 (GDF15) is a major secretory protein induced by mitochondrial dysfunction. In this article, we provide a brief overview of mitochondrial stress response and GDF15, and discuss the potential role of GDF15 in the pathophysiology of sepsis.

Keywords: GDF15; Inflammation; Integrated stress response; Mitochondrial stress; Sepsis

DOI: https://doi.org/10.1016/j.abb.2020.108668

Pigment Cell Melanoma Res. 2020 Nov 18.

NRF2 dependent stress defence in tumor antioxidant control and immune evasion.

José Pedro Friedmann Angeli, Svenja Meierjohann.

The transcription factor NRF2 is known as the master regulator of the oxidative stress response. Tumor entities presenting oncogenic activation of NRF2, such as lung adenocarcinoma, are associated with drug resistance, and accumulating evidence demonstrates its involvement in immune evasion. In other cancer types, the KEAP/NRF2 pathway is not commonly mutated, but NRF2 is activated by other means such as radiation, oncogenic activity, cytokines or other pro-oxidant triggers characteristic of the tumor niche. The obvious effect of stress-activated NRF2 is the protection from oxidative or electrophilic damage and the adaptation of the tumor metabolism to changing conditions. However, data from melanoma also reveal a role of NRF2 in modulating differentiation and suppressing anti-tumor immunity. This review summarizes the function of NRF2 in this tumor entity and discusses the implications for current tumor therapies.

DOI: https://doi.org/10.1111/pcmr.12946

Rheumatology (Oxford). 2020 Nov 12. pii: keaa670. [Epub ahead of print]

Tofacitinib counteracts IL-6 overexpression induced by deficient autophagy: implications in Sjögren's syndrome.

María-José Barrera, Sergio Aguilera, Isabel Castro, Soledad Matus, Patricia Carvajal, Claudio Molina, Sergio González, Daniela Jara, Marcela Hermoso, María-Julieta González.

OBJECTIVE: Altered homeostasis of salivary gland (SG) epithelial cells in Sjögren's syndrome (SS) could be the initiating factor that leads to inflammation, secretory dysfunction and autoimmunity. Autophagy is an important homeostatic mechanism, whose deficiency is associated with inflammation and accumulation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) components. We aimed to evaluate whether autophagy is altered in labial SG (LSG) epithelial cells from primary SS (pSS) patients and whether this contributes to inflammation through the JAK-STAT pathway. Furthermore, we investigated the anti-inflammatory effect of the JAK inhibitor tofacitinib in autophagy-deficient (ATG5 knockdown) three-dimensional (3D)-acini.
METHODS: We analysed LSG biopsies from 12 pSS patients with low focus score and 10 controls. ATG5-deficient 3D-acini were generated and incubated with IL-6 in the presence or absence of tofacitinib. Autophagy markers, pro-inflammatory cytokine expression, and JAK-STAT pathway activation were evaluated by PCR or western blot, along with correlation analyses between the evaluated markers and clinical parameters.
RESULTS: LSG from pSS patients showed increased p62 and decreased ATG5 expression, correlating negatively with increased activation of JAK-STAT pathway components (pSTAT1 and pSTAT3). Increased expression of STAT1 and IL-6 correlated with EULAR Sjögren's syndrome disease activity index and the presence of anti-Ro antibodies. ATG5-deficient 3D-acini reproduced the findings observed in LSG from pSS patients, showing increased expression of pro-inflammatory markers such as IL-6, which was reversed by tofacitinib.
CONCLUSION: Decreased expression of ATG5 in LSG epithelial cells from pSS patients possibly contributes to increased inflammation associated with JAK-STAT pathway activation, as evidenced in ATG5-deficient 3D-acini. Interestingly, these results suggest that tofacitinib could be used as an anti-inflammatory agent in pSS patients.

Keywords: IL-6; Sjögren’s syndrome; autophagy; epithelial cells; inflammation; tofacitinib

DOI: https://doi.org/10.1093/rheumatology/keaa670