Tumour suppressor Fus1 provides a molecular link between inflammatory response and mitochondrial homeostasis

Our plain-English summary of Tumour suppressor Fus1 provides a molecular link between inflammatory response and mitochondrial homeostasis, by R. Uzhachenko, N. Issaeva, K. Boyd, et al (The Journal of Pathology, 2012).

The study

• Authors: R. Uzhachenko, N. Issaeva, K. Boyd, S.V. Ivanov, D.P. Carbone, A.V. Ivanova
• Journal: The Journal of Pathology
• Published: 2012;227(4):456-69
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Fus1, encoded by a 3p21.3 tumour suppressor gene, is down-regulated, mutated or lost in the majority of inflammatory thoracic malignancies. The mitochondrial localization of Fus1 stimulated us to investigate how Fus1 modulates inflammatory response and mitochondrial function in a mouse model of asbestos-induced peritoneal inflammation. Asbestos treatment resulted in a decreased Fus1 expression in wild-type (WT) peritoneal immune cells, suggesting that asbestos exposure may compromise the Fus1-mediated inflammatory response. Untreated Fus1(-/-) mice had an ~eight-fold higher proportion of peritoneal granulocytes than Fus1(+/+) mice, pointing at ongoing chronic inflammation. Fus1(-/-) mice exhibited a perturbed inflammatory response to asbestos, reflected in decreased immune organ weight and peritoneal fluid protein concentration, along with an increased proportion of peritoneal macrophages. Fus1(-/-) immune cells showed augmented asbestos-induced activation of key inflammatory, anti-oxidant and genotoxic stress response proteins ERK1/2, NFκB, SOD2, γH2AX, etc. Moreover, Fus1(-/-) mice demonstrated altered dynamics of pro- and anti-inflammatory cytokine expression, such as IFNγ, TNFα, IL-1A, IL-1B and IL-10. 'Late' response cytokine Ccl5 was persistently under-expressed in Fus1(-/-) immune cells at both basal and asbestos-activated states. We observed an asbestos-related difference in the size of CD3(+) CD4(-) CD8(-) DN T cell subset that was expanded four-fold in Fus1(-/-) mice. Finally, we demonstrated Fus1-dependent basal and asbestos-induced changes in major mitochondrial parameters (ROS production, mitochondrial potential and UCP2 expression) in Fus1(-/-) immune cells and in Fus1-depleted cancer cells, thus supporting our hypothesis that Fus1 establishes its immune- and tumour-suppressive activities via regulation of mitochondrial homeostasis.

Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

In plain English

This was a laboratory study in mice and cultured cells; it did not study people. The authors injected crocidolite asbestos (1.0 mg per mouse) into the abdominal (peritoneal) cavity of normal mice and of mice lacking Fus1, a tumour suppressor gene. They examined the resulting inflammation 1, 2 and 7 days later. In normal mice, asbestos lowered Fus1 RNA levels in peritoneal immune cells about two-fold. Untreated Fus1-deficient mice already had more peritoneal granulocytes (21% versus 2.8%). After asbestos, Fus1-deficient mice had lower spleen and thymus weights and a higher share of macrophages (41.1% versus 30.4% at day 2). They also showed stronger markers of inflammation, oxidative stress and DNA damage, altered cytokine timing, and persistently low CCL5. At 48 hours, double-negative T cells made up 51.9% of their peritoneal T cells, versus 23.9% in normal mice. Mitochondrial measures (reactive oxygen species, membrane potential and UCP2) also differed, including in head and neck cancer cells with FUS1 reduced. The authors concluded that Fus1 loss resulted in a distorted asbestos-induced peritoneal inflammatory response.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment in genetically modified (Fus1 knockout) and normal mice, with additional cell-culture experiments
• Who was studied: Normal (Fus1+/+, wild-type) and Fus1-knockout (Fus1−/−) mice on a C57BL/6 background. Group sizes differed by analysis:
• The cytokine and T cell analyses used 5–7 mice per group.
• The Fus1 RNA measurement used seven asbestos-injected mice.
• The Western blot used two control and two asbestos-exposed mice per genotype.
  A head and neck cancer cell line (JHU012) with FUS1 depleted was also studied. The work was done at Vanderbilt University Medical Center, Nashville, USA.
• Exposure: A single intraperitoneal injection of crocidolite asbestos (UICC standard) suspended in saline, 1.0 mg per mouse. Control mice received saline (PBS). Mice were analysed 1, 2 and 7 days after injection.
• Main results:
  • In asbestos-exposed normal mice, Fus1 RNA in peritoneal immune cells was decreased about two-fold
  • Untreated (control) Fus1-knockout mice had a higher proportion of peritoneal granulocytes than untreated normal mice: 21 ± 0.78% versus 2.8 ± 0.85%, p less than or equal to 0.0005
  • Mean spleen and thymus weights were lower in Fus1-knockout mice than in normal mice at days 2 and 7 after asbestos
  • After asbestos, peritoneal macrophages made up a larger share in knockout mice. At day 2 they were 41.1 ± 3.1% in knockout versus 30.4 ± 2.6% in normal mice, p less than or equal to 0.0005. Differences were also reported at days 1 and 7.
  • At day 7 after asbestos, knockout mice showed granulomatous inflammation of the mesenteric fat with abundant Langhans-type giant cells
  • At 24 hours after asbestos, knockout peritoneal cells showed:
• higher activation of inflammatory regulators (pERK1/2, pNFκB);
• higher levels of anti-oxidant proteins (PRDX1, SOD2);
• greater activation of the DNA damage marker γH2AX.
  This was a Western blot comparison of two control and two exposed mice per genotype.
  • In knockout mice, IFNγ and TNFα were significantly lower than in normal mice at day 1, and higher at day 7
  • Ccl5 was expressed at a lower level in knockout peritoneal immune cells at all time points
  • At 48 hours after asbestos, CD4−CD8− double-negative T cells made up 51.9 ± 13.2% of peritoneal T cells in knockout mice, versus 23.9 ± 8.6% in normal mice, p less than 0.002
  • At day 7, double-negative T cells were 52.4 ± 4.3% in knockout mice versus 32.5 ± 10.8% in normal mice, with the p-value printed as p less than 0.069
  • The double-negative T cell difference was not found in other immune organs
  • Basal Ucp2 levels in peritoneal cells were about four-fold higher in knockout than in normal mice
  • After asbestos, knockout peritoneal cells generated significantly less reactive oxygen species (ROS) than normal cells
  • Basal mitochondrial membrane potential was higher in knockout peritoneal cells
  • In JHU012 head and neck cancer cells, FUS1 depletion produced a significant increase in ROS and mitochondrial membrane potential, together with UCP2 suppression
• The authors' conclusion: The authors concluded that systemic Fus1 loss resulted in a semi-inflammatory state of peritoneal cells in untreated mice and in a distorted asbestos-induced peritoneal inflammatory response. They suggested that Fus1 regulates inflammation through maintenance of mitochondrial homeostasis.

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Asbestos Exposure, Chronic Inflammation, Macrophage, Cytokine.

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