Monocyte progenitors give rise to multinucleated giant cells

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.

Progress of the Art of Macrophage Polarization and Different Subtypes in Mycobacterial Infection

“…E-cadherin is a necessary player in fusion, and its production can be stimulated by the activation of STAT6 through IL-4 or IL-13 pathway, similar to epithelialization under the circumstance of schistosome granulomas (38). However, the development of polyploid MGCs involves cell autonomous affliction of Toll-like receptor-elicited DNA damage, cell autonomous cell-cycle alterations, and impairment of p53 function by the potent antimicrobial effector, namely, NO, driving mitotic defects and multinucleation (35,39) (42,43). Unfortunately, the distinct role of MGCs in mycobacterial infection immune response remains as major gaps.…”

“…Mechanistically, they have distinguished the functional differences between M. bovis and MTb host-pathogen interplay and demonstrated that MPB70 from M. bovis and extracellular vesicles released by M. bovis -infected bMϕ promote Mϕ multinucleation ( 41 ). Startlingly, local adaptive immune response, particularly programmed cell death ligand-1, fatty acid, and cholesterol metabolism could take part in containing granuloma progression in human lung TB ( 42 , 43 ).…”

“…Unfortunately, the distinct role of MGCs in mycobacterial infection immune response remains as major gaps. MGCs may restrict mycobacterial cell-to-cell dissemination, involve in mycobacterial latency, or promote tissue destruction because of their high expression of extracellular matrix-degrading epithelioid macrophage marker molecules (EMMMs) ( 38 , 43 ). The maturation of MGCs supplies a restrictive environment for M. bovis .…”

Perinatal development of innate immune topology

“…Proper differentiation of tissue-resident immune cells along predefined pathways is a prerequisite for tissue development and regeneration. Yet at the same time, cellular transformation processes are subject to hijacking by ‘latent’ microorganisms like mycobacteria and herpes viruses for the creation of a chronic niche ( Lösslein et al, 2021 ).…”

Adipoclast: a multinucleated fat-eating macrophage

“…Multinucleated foam cells have been indeed observed as a result of high-fat diet in inflammatory sites such as the synovium [16]. Recent evidence shows that common monocyte progenitors accumulate cholesterol and lipids, which are required for MGC formation [17]. These studies suggest that a lipid rich microenvironment such as the white adipose tissue (WAT) can be 'fusogenic' for resident macrophages.…”