No conflicts of interest were declared.
Tumour suppressor Fus1 provides a molecular link between inflammatory response and mitochondrial homeostasis†
Article first published online: 6 JUN 2012
Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 227, Issue 4, pages 456–469, August 2012
How to Cite
Uzhachenko, R., Issaeva, N., Boyd, K., Ivanov, S. V., Carbone, D. P. and Ivanova, A. V. (2012), Tumour suppressor Fus1 provides a molecular link between inflammatory response and mitochondrial homeostasis. J. Pathol., 227: 456–469. doi: 10.1002/path.4039
- Issue published online: 10 JUL 2012
- Article first published online: 6 JUN 2012
- Accepted manuscript online: 18 APR 2012 06:44AM EST
- Manuscript Accepted: 7 APR 2012
- Manuscript Revised: 4 APR 2012
- Manuscript Received: 14 OCT 2011
- inflammatory response;
- DN T cells;
- mitochondrial membrane potential;
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.