Research Article: Storage lipid studies in tuberculosis reveal that foam cell biogenesis is disease-specific

Date Published: August 30, 2018

Publisher: Public Library of Science

Author(s): Valentina Guerrini, Brendan Prideaux, Landry Blanc, Natalie Bruiners, Riccardo Arrigucci, Sukhwinder Singh, Hsin Pin Ho-Liang, Hugh Salamon, Pei-Yu Chen, Karim Lakehal, Selvakumar Subbian, Paul O’Brien, Laura E. Via, Clifton E. Barry, Véronique Dartois, Maria Laura Gennaro, Christopher M. Sassetti.


Foam cells are lipid-laden macrophages that contribute to the inflammation and tissue damage associated with many chronic inflammatory disorders. Although foam cell biogenesis has been extensively studied in atherosclerosis, how these cells form during a chronic infectious disease such as tuberculosis is unknown. Here we report that, unlike the cholesterol-laden cells of atherosclerosis, foam cells in tuberculous lung lesions accumulate triglycerides. Consequently, the biogenesis of foam cells varies with the underlying disease. In vitro mechanistic studies showed that triglyceride accumulation in human macrophages infected with Mycobacterium tuberculosis is mediated by TNF receptor signaling through downstream activation of the caspase cascade and the mammalian target of rapamycin complex 1 (mTORC1). These features are distinct from the known biogenesis of atherogenic foam cells and establish a new paradigm for non-atherogenic foam cell formation. Moreover, they reveal novel targets for disease-specific pharmacological interventions against maladaptive macrophage responses.

Partial Text

Formation of foam cells (lipid-laden macrophages) is a manifestation of maladaptive responses occurring during chronic inflammatory conditions [1]. The best-studied case is that of atherosclerosis. There, retention of lipoproteins in the arterial intima triggers extravasation of circulating monocytes and subsequent accumulation of lipids, predominantly cholesteryl esters, in the cytoplasm of monocyte-derived macrophages. The resulting foam cells exhibit impaired immune functions; they also produce pro-inflammatory mediators and release cellular content upon death [2]. By maintaining inflammation and failing to resolve it, foam cells contribute to a chronic inflammatory state and consequently to tissue damage [2, 3]. Foam cells are observed well beyond the hyperlipidemia associated with atherosclerosis: these lipid-laden macrophages are found in many diseases of non-infectious (e.g., autoimmune) and infectious (e.g., HIV, tuberculosis) etiology, where foam cells are often central to pathogenesis [4]. Since these diseases are associated with chronic inflammation rather than hyperlipidemia, the mechanisms triggering foam cell formation in these pathologies may differ from those occurring during atherosclerosis. Whether that is the case is currently unknown.

The present report shows that the dominant type of storage lipid found in the necrotic and foam-cell-rich regions of tuberculous granulomas is TAG; moreover, the accumulation of this lipid class in M. tuberculosis-infected macrophages is driven by TNF receptor signaling, by downstream activation of the metabolic master regulator mTORC1, and by the caspase cascade. Both mTORC1 signaling and caspase activation regulate transcription factors (sterol regulatory element-binding proteins, SREBPs) involved in TAG biosynthesis [40, 41, 44, 51], and both block autophagy [42, 52], which is a major cellular lipid catabolic process [53]. Thus, increased TAG biosynthesis and/or inhibition of autophagy may be driving TAG accumulation in macrophages during M. tuberculosis infection. By characterizing the chemical nature of the dominant storage lipid in tuberculous foam cells and the underlying accumulation mechanisms, our work opens a new avenue of investigation into relationships between the human host and its deadliest pathogen [54].