Cholesterol crystal-mediated inflammation in alveolar macrophages: an emerging role in idiopathic lung fibrosis?
Final Report Abstract
Idiopathic pulmonary fibrosis is a chronic lung disease characterized by progressive scarring of the lung, eventually causing respiratory failure and death. It currently affects 80,000-111,000 people in Europe and has no cure yet. Alveolar macrophages are important immune cells involved in the defence against microorganisms. Moreover, they are partially responsible for the recycling of lung surfactant, a complex of lipids and proteins that allow for respiration and the exchange of gases to occur. Thus, altered activity of alveolar macrophages may lead to surfactant accumulation. Among lipids, cholesterol seems to play a key role, since animal models of pulmonary fibrosis show accumulation of cholesterol in macrophages. Moreover, accumulation of structures similar to cholesterol crystals (CC), have been observed in mouse lungs from different lung disease models. We hypothesized that altered cholesterol metabolism leads to an inflammatory response in alveolar macrophage, thus contributing to lung fibrosis. To test this hypothesis, the project specifically aimed to: characterize the molecular mechanism of CC formation and uptake in alveolar macrophages and potential activation of inflammatory processes in cell cultures; detect altered lung lipid metabolic mechanisms and activation of inflammatory response in a mouse model that develops lung fibrosis with age; validate the results in lung samples from pulmonary fibrosis patients. Our results showed that macrophage-like cells can uptake and metabolise cholesterol from CC, and internalize pre-formed CC. This uptake involves CD36 receptor and cause a sterile activation of inflammatory response and release of inflammatory proteins. In the mouse model, changes in different lipid classes were found and cholesterol metabolism showed age-related changes, along with accumulation of crystals in alveolar macrophages and activation of inflammatory response in older mice. Moreover, we found increased levels of cholesterol in lung samples of patients compared to healthy donors, together with decreased levels of CD36 and increased levels of proteins promoting cholesterol efflux. Taken together, these data highlight a possible role of cholesterol metabolism and cholesterol-mediated inflammation in the context of lung fibrosis. Given the urgency of an effective therapy for idiopathic pulmonary fibrosis, the growing interest of the medical community on the role of lipid metabolism in the development of lung fibrosis, and the translational approach proposed, the results of this project could provide new insights into the development of therapeutic targets and diagnostic tools.
Publications
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Cholesterol crystal-mediated inflammation in alveolar macrophages: a new potential therapy target for lung fibrosis. DZL Academy Symposium 2022 (Rauischholzhausen, Germany)
Giambelluca S., Vaso M., Ochs M. & Lopez-Rodriguez E.
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Resting time after phorbol 12-myristate 13-acetate in THP-1 derived macrophages provides a non-biased model for the study of NLRP3 inflammasome. Frontiers in Immunology, 13.
Giambelluca, Sonia; Ochs, Matthias & Lopez-Rodriguez, Elena
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Crystal-mediated inflammation in lung fibrosis. Gordon Research Conference - Lung Development, Injury and Repair 2023 (Waterville Valley, NH, United States)
Giambelluca S., Vaso M., Ochs M. & Lopez-Rodriguez E.
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Crystal-mediated inflammation in alveolar macrophages of a mouse model of lung fibrosis. ERS Lung Science Conference 2024 (Estoril, Portugal)
Vaso M., Ochs M., Winder C., Lin W., Dunn W.B., Lopez-Rodriguez E. & Giambelluca S.
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Cholesterol-mediated inflammation activation in alveolar macrophages. BMC Biology, 23(1).
Giambelluca, Sonia; Ochs, Matthias & Lopez-Rodriguez, Elena
