Fra-2–expressing macrophages promote lung fibrosis

Ucero, Álvaro C.; Bakiri, Latifa; Roediger, Ben; Suzuki, M.; Jiménez, María; Mandal, Pratyusha; Braghetta, Paola; Bonaldo, Paolo; Paz‐Ares, Luis; Fustero-Torre, Coral; Ximénez-Embún, Pilar; Hernández, Ana Isabel; Megı́as, Diego; Wagner, Erwin F.

doi:10.1172/jci125366

Cited by 87 publications

(62 citation statements)

References 75 publications

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“…We therefore hypothesized that ILC3-derived GM-CSF might not only inhibit a fibroblast/myofibroblast-like phenotype in macrophages, but also their ability to stimulate mesenchymal cells. In keeping with this, colonic macrophages from ILC-depleted mice showed an increase in Col6a1 , Col6a2 , and Col6a3 transcripts ( Figure 6 B) that together form trimers that make up collagen type VI, previously shown to promote myofibroblast activation in the context of lung fibrosis ( Ucero et al., 2019 ). We also found a marked increase in several growth factor transcripts in colonic macrophages ( Figure 6 F) and colonic levels of Pdgfb were globally elevated in the absence of ILCs ( Figure S6 E).…”

Section: Resultssupporting

confidence: 81%

“…Remarkably, depletion of ILCs or neutralization of GM-CSF in the context of enteropathic infection or barrier breach-induced inflammation resulted in enhanced expression of collagen subunits by macrophages, as well as production of fibroblast-stimulating growth factors, including PDGF-BB. Macrophage production of collagen has been previously described in human macrophages in vitro and in atherosclerotic plaques ( Schnoor et al., 2008 ; Weitkamp et al., 1999 ), in mouse models of kidney ( Meng et al., 2016 ) and lung injury ( Ucero et al., 2019 ), and in skin wounds ( Sinha et al., 2018 ), consistent with a transition to a fibroblast/myofibroblast phenotype. Indeed, in the latter study, fate-mapping suggested that two-thirds of granulation tissue fibroblasts in the wound were of myeloid origin ( Sinha et al., 2018 ).…”

Section: Discussionmentioning

confidence: 87%

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GM-CSF Calibrates Macrophage Defense and Wound Healing Programs during Intestinal Infection and Inflammation

et al. 2020

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Summary Macrophages play a central role in intestinal immunity, but inappropriate macrophage activation is associated with inflammatory bowel disease (IBD). Here, we identify granulocyte-macrophage colony stimulating factor (GM-CSF) as a critical regulator of intestinal macrophage activation in patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis. We find that GM-CSF drives the maturation and polarization of inflammatory intestinal macrophages, promoting anti-microbial functions while suppressing wound-healing transcriptional programs. Group 3 innate lymphoid cells (ILC3s) are a major source of GM-CSF in intestinal inflammation, with a strong positive correlation observed between ILC or CSF2 transcripts and M1 macrophage signatures in IBD mucosal biopsies. Furthermore, GM-CSF-dependent macrophage polarization results in a positive feedback loop that augmented ILC3 activation and type 17 immunity. Together, our data reveal an important role for GM-CSF-mediated ILC-macrophage crosstalk in calibrating intestinal macrophage phenotype to enhance anti-bacterial responses, while inhibiting pro-repair functions associated with fibrosis and stricturing, with important clinical implications.

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Section: Resultssupporting

confidence: 81%

Section: Discussionmentioning

confidence: 87%

GM-CSF Calibrates Macrophage Defense and Wound Healing Programs during Intestinal Infection and Inflammation

et al. 2020

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“…Upon survey of the transcriptomes of Mo-AMs and TR-AMs from mice that were treated intratracheally (i.t.) with bleomycin, we were particularly interested in ApoE because (a) it is one of the most differentially expressed genes in Mo-AMs as compared with TR-AMs from bleomycin-treated lungs and (b) its abundance in Mo-AMs is much greater than several previously defined profibrotic mediators in this AM subtype, such as PDGF and Collagen VI (10,23,24).…”

Section: Resultsmentioning

confidence: 99%

Monocyte-derived alveolar macrophage apolipoprotein E participates in pulmonary fibrosis resolution

Jiang¹,

Banerjee²,

Xie³

et al. 2020

JCI Insight

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“…The only other mouse model purported to represent CTD‐PAH is the Fra‐2–Tg mouse . While that model does share many features with scleroderma, Fra‐2–Tg mice have severe lung fibrosis and inflammation with associated pulmonary hypertension more akin to World Health Organization group III pulmonary hypertension. Moreover, Fra‐2–Tg mice have a much lower RVSP elevation (RVSP ~30 mm Hg) than TNF‐Tg mice (RVSP 50–100 mm Hg).…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor Induces Obliterative Pulmonary Vascular Disease in a Novel Model of Connective Tissue Disease–Associated Pulmonary Arterial Hypertension

Bell

White

García-Hernández

et al. 2020

Arthritis & Rheumatology

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Objective. Connective tissue disease (CTD)-associated pulmonary arterial hypertension (PAH) is the second most common etiology of PAH and carries a poor prognosis. Recently, it has been shown that female human tumor necrosis factor (TNF)-transgenic (Tg) mice die of cardiopulmonary disease by 6 months of age. This study was undertaken to characterize this pathophysiology and assess its potential as a novel model of CTD-PAH. Methods. Histologic analysis was performed on TNF-Tg and wild-type (WT) mice to characterize pulmonary vascular and right ventricular (RV) pathology (n = 40 [4-5 mice per group per time point]). Mice underwent right-sided heart catheterization (n = 29) and micro-computed tomographic angiography (n = 8) to assess vascular disease. Bone marrow chimeric mice (n = 12), and anti-TNF-treated mice versus placebo-treated mice (n = 12), were assessed. RNA sequencing was performed on mouse lung tissue (n = 6). Results. TNF-Tg mice displayed a pulmonary vasculopathy marked by collagen deposition (P < 0.001) and vascular occlusion (P < 0.001) with associated RV hypertrophy (P < 0.001) and severely increased RV systolic pressure (mean ± SD 75.1 ± 19.3 mm Hg versus 26.7 ± 1.7 mm Hg in WT animals; P < 0.0001). TNF-Tg mice had increased α-smooth muscle actin (α-SMA) staining, which corresponded to proliferation and loss of von Willebrand factor (vWF)-positive endothelial cells (P < 0.01). There was an increase in α-SMA-positive, vWFpositive cells (P < 0.01), implicating endothelial-mesenchymal transition. Bone marrow chimera experiments revealed that mesenchymal but not bone marrow-derived cells are necessary to drive this process. Treatment with anti-TNF therapy halted the progression of disease. This pathology closely mimics human CTD-PAH, in which patient lungs demonstrate increased TNF signaling and significant similarities in genomic pathway dysregulation. Conclusion. The TNF-Tg mouse represents a novel model of CTD-PAH, recapitulates key disease features, and can serve as a valuable tool for discovery and assessment of therapeutics.

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Fra-2–expressing macrophages promote lung fibrosis

Cited by 87 publications

References 75 publications

GM-CSF Calibrates Macrophage Defense and Wound Healing Programs during Intestinal Infection and Inflammation

GM-CSF Calibrates Macrophage Defense and Wound Healing Programs during Intestinal Infection and Inflammation

Monocyte-derived alveolar macrophage apolipoprotein E participates in pulmonary fibrosis resolution

Tumor Necrosis Factor Induces Obliterative Pulmonary Vascular Disease in a Novel Model of Connective Tissue Disease–Associated Pulmonary Arterial Hypertension

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