IL-1β- and IL-4-polarized macrophages have opposite effects on adipogenesis of intramuscular fibro-adipogenic progenitors in humans

Abstract

Intramuscular fat deposition represents a negative prognostic factor for several myopathies, metabolic diseases and aging. Fibro-adipogenic progenitors (FAPs) are considered as the main source of intramuscular adipocytes, but the mechanisms controlling their adipogenic potential are still not elucidated in humans. The aim of this study was to explore the regulation of human FAP adipogenesis by macrophages. We found that CD140a-expressing FAPs were located close to CD68 positive macrophages in muscles from patients with Duchenne muscular dystrophy (DMD). This strongly suggests a potential interaction between FAPs and macrophages in vivo. Isolated human primary FAPs were then differentiated in the presence of conditioned media obtained from primary blood monocyte-polarized macrophages. Molecules released by IL-1β-polarized macrophages (M(IL-1β)) drastically reduced FAP adipogenic potential as assessed by decreased cellular lipid accumulation and reduced gene expression of adipogenic markers. This was associated with an increased gene expression of pro-inflammatory cytokines in FAPs. Conversely, factors secreted by IL-4-polarized macrophages (M(IL-4)) enhanced FAP adipogenesis. Finally, the inhibition of FAP adipocyte differentiation by M(IL-1β) macrophages requires the stimulation of Smad2 phosphorylation of FAPs. Our findings identify a novel potential crosstalk between FAPs and M(IL-1β) and M(IL-4) macrophages in the development of adipocyte accumulation in human skeletal muscles.

Genetic reduction of the extracellular matrix protein versican attenuates inflammatory cell infiltration and improves contractile function in dystrophic mdx diaphragm muscles

“…To demonstrate that versican synthesis and remodelling are associated with inflammation and regeneration in dystrophic diaphragm muscles, serial sections were used to co-localize versikine with desmin or CD68. Desmin is expressed in activated satellite cells and newly regenerated muscle fibres 55 , whilst CD68 is expressed by infiltrating monocytes and macrophages in various models of muscle damage, includes dystrophic muscles from mdx mice and patients with DMD 56,57,99,100 . Serial sections were used, because the anti-verskine, anti-CD68 (Abcam; ab125212) and anti-desmin (Abcam; ab15200) antibodies were all raised in the same species (rabbit).…”

Role of Metabolic Stress and Exercise in Regulating Fibro/Adipogenic Progenitors

“…Specifically, during chronic muscle damage, macrophage-derived TGF-β1, inhibits TNF-mediated FAP, and instead induce their fibrogenic differentiation and consequent extracellular matrix deposition (Lemos et al, 2015;Davies et al, 2016;Fiore et al, 2016;Juban et al, 2018). Similarly, Moratal et al (2018) report that IL-1β-activated macrophages and IL-4-polarized macrophages have opposite effects on FAP differentiation into adipocytes in vitro, which was dependent on Smad2 phosphorylation in FAPs. Thus, under chronic inflammatory conditions associated with several metabolic disorders, signals that regulate FAP apoptosis and inhibit proliferation are perturbed, leading to a chronic state of remodeling which ultimately results in fibro/fatty tissue accumulation.…”

Review: Enhancing intramuscular fat development via targeting fibro-adipogenic progenitor cells in meat animals

“…Immune cells also regulate the fates of intramuscular FAPs. Fibro-adipogenic progenitors and macrophages (CD68 positive) are located in very close proximity in human degenerating skeletal muscles (Moratal et al, 2018), suggesting a potential interaction between intramuscular FAPs and macrophages in vivo.…”

“…The transition from a pro-to anti-inflammatory status in the niche profoundly affects intramuscular adipogenesis in mice (Dammone et al, 2018). Indirect co-culture with conditioned media showed that cytokines secreted by IL-1β-polarized macrophages drastically reduce intramuscular FAP adipogenic potential via stimulating SMAD2 (SMAD family member 2) signaling, and factors released by IL-4-polarized macrophages conversely enhance cellular lipid accumulation and expression of adipogenic markers, thus facilitating intramuscular FAPs adipogenesis (Moratal et al, 2018).…”