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Macrophages promote collagen fibrillogeneis through modulation of fibroblast circadian rhythms

ABSTRACT: Collagen deposition in fibroblasts, the primary collagen-producing cells, is regulated by both macrophages and the circadian rhythm, although how these regulatory processes interact with one another is unknown. Here, we reveal that macrophage-fibroblast interaction enhances collagen deposition which requires a functional circadian rhythm. This response is also dependent on macrophage polarisation status, where M0 (naïve) and M1 (pro-inflammatory) macrophages require direct cell-cell contact; whereas M2 (anti-inflammatory) macrophages utilise an additional mechanism through secreted soluble factors that strengthen circadian rhythms and significantly increase collagen deposition in fibroblasts, independent of cell-cell contact. Using mass spectrometry proteomics analysis, we identified PDGFA as a key factor in induction of circadian amplitude in fibroblasts.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Macrophage

SUBMITTER: Joan Chang

LAB HEAD: Joan Chang

PROVIDER: PXD061123 | Pride | 2026-08-07

REPOSITORIES: Pride

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			Action	DRS
	20240426_ChangJ_LumosDDA_60min_KL08.index	Other
	20240426_ChangJ_LumosDDA_60min_KL08.raw	Raw
	20240426_ChangJ_LumosDDA_60min_KL09.index	Other
	20240426_ChangJ_LumosDDA_60min_KL09.raw	Raw
	20240426_ChangJ_LumosDDA_60min_KL10.index	Other

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Project description:Rationale: Expansion and activation of cardiac fibroblasts contributes to adverse remodeling, fibrosis and dysfunction in the pressure-overloaded heart. Although early fibroblast TGF-β/Smad3 activation protects the pressure overloaded heart by preserving the matrix, sustained TGF-β activation may be deleterious, accentuating fibrosis and dysfunction. Thus, endogenous mechanisms that negatively regulate the TGF- response in fibroblasts may be required to protect from progressive fibrosis and adverse remodeling. Objective: To study the role of fibroblast-specific induction of Smad7, an inhibitory Smad that restrains TGF-β signaling, in regulation of fibrosis, remodeling and dysfunction of the pressure-overloaded heart. Methods and Results: In a mouse model of pressure overload induced through transverse aortic constriction (TAC), Smad7 was upregulated in cardiac myofibroblasts. Mice with myofibroblast-specific loss of Smad7 (MFS7KO) had increased mortality, accentuated systolic dysfunction and dilative remodeling, and accelerated diastolic dysfunction in response to TAC. Increased dysfunction in MFS7KO hearts was associated with accentuated fibrosis and increased collagen denaturation, in the absence of effects on cardiomyocyte death. Secretomic analysis showed that Smad7 loss accentuates secretion of structural collagens and matricellular proteins, and markedly increases secretion of matrix metalloproteinase-2 (MMP2). In a 3D model of fibroblasts populating collagen lattices the effects of Smad7 on fibroblast-induced collagen denaturation and pad contraction were partly mediated via MMP2 downregulation. Surprisingly, MFS7KO mice also exhibited significant macrophage expansion caused by paracrine actions of Smad7 null fibroblasts that stimulate macrophage proliferation and fibrogenic activation. Secretomic analysis and in vitro experiments suggested that macrophage activation involves the combined effects of the fibroblast-derived matricellular proteins CD5L, SPARC, CTGF, ECM1 and TGFBI. Conclusions: The anti-fibrotic effects of Smad7 in the pressure-overloaded heart protect from dysfunction and involve not only reduction in collagen deposition, but also suppression of MMP2-mediated matrix denaturation and paracrine effects that suppress macrophage activation through inhibition of matricellular proteins.

Project description:Rationale: Expansion and activation of cardiac fibroblasts contributes to adverse remodeling, fibrosis and dysfunction in the pressure-overloaded heart. Although early fibroblast TGF-β/Smad3 activation protects the pressure overloaded heart by preserving the matrix, sustained TGF-β activation may be deleterious, accentuating fibrosis and dysfunction. Thus, endogenous mechanisms that negatively regulate the TGF- response in fibroblasts may be required to protect from progressive fibrosis and adverse remodeling. Objective: To study the role of fibroblast-specific induction of Smad7, an inhibitory Smad that restrains TGF-β signaling, in regulation of fibrosis, remodeling and dysfunction of the pressure-overloaded heart. Methods and Results: In a mouse model of pressure overload induced through transverse aortic constriction (TAC), Smad7 was upregulated in cardiac fibroblasts and myofibroblasts. Mice with myofibroblast-specific loss of Smad7 (MFS7KO) had increased mortality, accentuated systolic dysfunction and dilative remodeling, and accelerated diastolic dysfunction in response to TAC. Increased dysfunction in MFS7KO hearts was associated with accentuated fibrosis and increased collagen denaturation, in the absence of effects on cardiomyocyte death. Secretomic analysis showed that Smad7 loss accentuates secretion of structural collagens and matricellular proteins, and markedly increases secretion of matrix metalloproteinase-2 (MMP2). In a 3D model of fibroblasts populating collagen lattices the effects of Smad7 on fibroblast-induced collagen denaturation and pad contraction were partly mediated via MMP2 downregulation. Surprisingly, MFS7KO mice also exhibited significant macrophage expansion caused by paracrine actions of Smad7 null fibroblasts that stimulate macrophage proliferation and fibrogenic activation. Secretomic analysis and in vitro experiments suggested that macrophage activation involves the combined effects of the fibroblast-derived matricellular proteins CD5L, SPARC, CTGF, ECM1 and TGFBI. Conclusions: The anti-fibrotic effects of Smad7 in the pressure-overloaded heart protect from dysfunction and involve not only reduction in collagen deposition, but also suppression of MMP2-mediated matrix denaturation and paracrine effects that suppress macrophage activation through inhibition of matricellular proteins.

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Macrophages promote collagen fibrillogeneis through modulation of fibroblast circadian rhythms

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