Abstract
Mycobacterium tuberculosis (Mtb) infects macrophages and macrophage-derived foam cells, a hallmark of granulomata in tuberculous lesions. We analyzed the effects of lipid accumulation in human primary macrophages and quantified strong triglyceride and phospholipid remodeling which depended on the dietary fatty acid used for the assay. The enrichment of >70% in triglyceride and phospholipids can alter cell membrane properties, signaling and phagocytosis in macrophages. In conventional macrophage cultures, cells are heterogeneous, small or large macrophages. In foam cells, a third population of 30% of cells with increased granularity can be detected. We found that foam cell formation is heterogenous and that lipid accumulation and foam cell formation reduces the phagocytosis of Mtb. Under the conditions tested, cell death was highly prevalent in macrophages, whereas foam cells were largely protected from this effect. Foam cells also supported slower Mtb replication, yet this had no discernible impact on the intracellular efficacy of four different antitubercular drugs. Foam cell formation had a significant impact in the inflammatory potential of the cells. TNF-α, IL-1β, and prototypical chemokines were increased. The ratio of inflammatory IL-1β, TNF-α, and IL-6 vs. anti-inflammatory IL-10 was significantly higher in response to Mtb vs. LPS, and was increased in foam cells compared to macrophages, suggestive of increased pro-inflammatory properties. Cytokine production correlated with NF-κB activation in our models. We conclude that foam cell formation reduces the host cell avidity for, and phagocytosis of, Mtb while protecting the cells from death. This protective effect is associated with enhanced inflammatory potential of foam cells and restricted intracellular growth of Mtb.
Highlights
Foam cell macrophages have been described in varied human pathologies from the early twentiethcentury
The phagocyte system in Mycobacterium tuberculosis (Mtb) disease is highly heterogeneous and in addition to macrophages, the cells of the family adopt specialized phenotypes recognized as epithelioid cells, foam cell macrophages and multinucleated Langhans giant cells
We set out to assess the phagocytic ability of macrophages and fatty-acid-induced foam cells, using primary monocytederived macrophages as well as macrophages from THP-1 reporter cell lines
Summary
Foam cell macrophages have been described in varied human pathologies from the early twentiethcentury. Our knowledge about the composition and origin of lipids that accumulate in foam cell macrophages and their effects in immunity remain poorly defined. Foam cells appear in a variety of conditions where macrophages need to dispose of excessive lipids, and these can be of different nature (Chistiakov et al, 2017; Guerrini and Gennaro, 2019). Atherosclerosis is not their only arena and foam cells are a particular feature of tuberculous infection and caseation, a hallmark of persistent mycobacterial immune reactions (Peyron et al, 2008; Jaisinghani et al, 2018). A role for IFN-γ in this process has been shown, as well as for lipids derived from the host and the bacterium (Knight et al, 2018)
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