Abstract
The immune response to mycobacteria is characterized by granuloma formation, which features multinucleated giant cells as a unique macrophage type. We previously found that multinucleated giant cells result from Toll-like receptor-induced DNA damage and cell autonomous cell cycle modifications. However, the giant cell progenitor identity remained unclear. Here, we show that the giant cell-forming potential is a particular trait of monocyte progenitors. Common monocyte progenitors potently produce cytokines in response to mycobacteria and their immune-active molecules. In addition, common monocyte progenitors accumulate cholesterol and lipids, which are prerequisites for giant cell transformation. Inducible monocyte progenitors are so far undescribed circulating common monocyte progenitor descendants with high giant cell-forming potential. Monocyte progenitors are induced in mycobacterial infections and localize to granulomas. Accordingly, they exhibit important immunological functions in mycobacterial infections. Moreover, their signature trait of high cholesterol metabolism may be piggy-backed by mycobacteria to create a permissive niche.
Highlights
The immune response to mycobacteria is characterized by granuloma formation, which features multinucleated giant cells as a unique macrophage type
We previously found that MΦ progenitors have a higher potential than mature MΦ to undergo transformation into multinuclear giant cells (MGC) upon infection with mycobacteria or TLR2 stimulation (Fig. 1a and Herrtwich et al.)[9]
CMoP were potent, and quite specific MGC progenitors, since besides absolute quantity, the relative proportion of common monocyte progenitor (cMoP)-derived MGC was increased compared to MC (Figs. 1d, g and Supplementary Fig. 1c)
Summary
The immune response to mycobacteria is characterized by granuloma formation, which features multinucleated giant cells as a unique macrophage type. Monocyte progenitors are induced in mycobacterial infections and localize to granulomas They exhibit important immunological functions in mycobacterial infections. Their signature trait of high cholesterol metabolism may be piggy-backed by mycobacteria to create a permissive niche. Dissection of the MGC pedigree seems important, regarding the recent revolution in understanding MΦ development It remains to be resolved, if MGC are the progeny of a specific cell lineage or subset, and what metabolic preconditions might determine the differentiation path towards an MGC. We provide firm evidence for a so far unappreciated role of monocyte progenitors in mycobacterial infections They inextricably integrate progenitor characteristics, such as high proliferative activity and low apoptosis, with specific functions in mycobacterial immunity
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