Heterogeneity of foam cell biogenesis across diseases.

UNLABELLED: Foam cells are dysfunctional, lipid-laden macrophages associated with chronic inflammation of infectious and non-infectious origin. For decades, the paradigm of foam cell biology has been atherogenesis, in which macrophages accumulate cholesteryl esters. Our previous work showed that foam cells in tuberculous lung lesions are surprisingly triglyceride-rich, suggesting multiple modalities of foam cell biogenesis. In the present study, we used matrix-assisted laser desorption/ionization mass spectrometry imaging to assess the spatial distribution of storage lipids relative to foam-cell-rich areas in murine lungs infected with the fungal pathogen Cryptococcus neoformans and in human papillary renal cell carcinoma resection tissues. We also analyzed neutral lipid content and the transcriptional program of lipid-laden macrophages generated under corresponding in vitro conditions. The in vivo data were consistent with in vitro findings showing that C. neoformans -infected macrophages accumulated triglycerides, while macrophages exposed to human renal cell carcinoma-conditioned medium accumulated both triglycerides and cholesteryl esters. Moreover, macrophage transcriptome analyses provided evidence for condition-specific metabolic remodeling. The in vitro data also showed that although both Mycobacterium tuberculosis and C. neoformans infections induced triglyceride accumulation in macrophages, they did so by different molecular mechanisms, as evidenced by different sensitivity of lipid accumulation to the drug rapamycin and the characteristics of macrophage transcriptome remodeling. Collectively, these data demonstrate that the mechanisms of foam cell formation are specific to the disease microenvironment. Since foam cells have been regarded as targets of pharmacological intervention in several diseases, recognizing that their formation is disease-specific opens new research directions of biomedical significance.

SIGNIFICANCE STATEMENT: Chronic inflammatory states of infectious and non-infectious etiology are associated with dysfunctional immune responses. Primary contributors are foam cells, lipid-laden macrophages exhibiting impaired or pathogenic immune functions. In contrast with the long-standing paradigm derived from atherosclerosis in which foam cells are cholesterol-laden, our work demonstrates that foam cells are heterogeneous. Utilizing bacterial, fungal, and cancer models, we show that foam cells may accumulate various storage lipids (triglycerides and/or cholesteryl esters) by mechanisms that depend on disease-specific microenvironments. Thus, we present a new framework for foam cell biogenesis in which the atherosclerosis paradigm represents only a specific case. Since foam cells are a potential therapeutic target, understanding their mechanisms of biogenesis will provide knowledge needed for novel therapeutic approaches.