Foam Cell Formation In Vivo Converts Macrophages to a Pro-Fibrotic Phenotype

Abstract

Formation of foam cell macrophages, which sequester extracellular modified lipids, is a key event in atherosclerosis. How lipid loading affects macrophage phenotype is controversial, with evidence suggesting either pro- or anti-inflammatory consequences. To investigate this further, we compared the transcriptomes of foamy and non-foamy macrophages that accumulate in the subcutaneous granulomas of fed-fat ApoE null mice and normal chow fed wild-type mice in vivo. Consistent with previous studies, LXR/RXR pathway genes were significantly over-represented among the genes up-regulated in foam cell macrophages. Unexpectedly, the hepatic fibrosis pathway, associated with platelet derived growth factor and transforming growth factor-β action, was also over-represented. Several collagen polypeptides and proteoglycan core proteins as well as connective tissue growth factor and fibrosis-related FOS and JUN transcription factors were up-regulated in foam cell macrophages. Increased expression of several of these genes was confirmed at the protein level in foam cell macrophages from subcutaneous granulomas and in atherosclerotic plaques. Moreover, phosphorylation and nuclear translocation of SMAD2, which is downstream of several transforming growth factor-β family members, was also detected in foam cell macrophages. We conclude that foam cell formation in vivo leads to a pro-fibrotic macrophage phenotype, which could contribute to plaque stability, especially in early lesions that have few vascular smooth muscle cells.

A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

“…Oxidized phospholipid treatment also causes alternative activation and TGF-β secretion in human MØs [52]. Consistent with this report, recent work demonstrates that foam cell formation in vivo favors the development of a pro-fibrotic MØ activation profile [71, 72]. These studies, along with our results, suggest that lipid exposure or uptake in MØs may be important.…”

Phosphocholine‐containing ligands direct CRP induction of M2 macrophage polarization independent of T cell polarization: Implication for chronic inflammatory states

“…Macrophages take up oxidized lipids by a variety of receptors, including via CRP if the lipids bear PC. The resultant formation of foam cells may include their conversion into a pro‐fibrotic phenotype as we have shown here. In that way and others, macrophages may be important effectors of the pathologic stages in atherosclerosis.…”

Myelin as an inflammatory mediator: Myelin interactions with complement, macrophages, and microglia in spinal cord injury

“…For example, in active MS lesions, anti-inflammatory marker expression predominates on foam cell macrophages in the lesion center and inner rim, while proinflammatory marker expression is more widespread (Boven et al, 2006;Vogel et al, 2013). Similarly, a more recent evaluation of foam cells within the context of the M1/M2 macrophage paradigm observed a full range of M1-M2 foam cell activation states depending on the microenvironments from which the cells were isolated (Thomas, Eijgelaar, Daemen, & Newby, 2015a;2015b). In the case of SCI, two environmental cues that may promote M1 polarization in the presence of myelin are TNF and intracellular iron, perhaps reflective of the increased hemorrhage in SCI lesions relative to those in MS (Kroner et al, 2014).…”