Osteopontin Links Myeloid Activation and Disease Progression in Systemic Sclerosis

Gao, Xia; Jia, Guiquan; Guttman, Anna; DePianto, Daryle J.; Morshead, Katrina B.; Sun, Kan; Ramamoorthi, Nandhini; Heiden, Jason A. Vander; Modrušan, Zora; Wolters, Paul J.; Jahreis, Angelika; Arron, Joseph R.; Khanna, Dinesh; Ramalingam, Thirumalai R.

doi:10.1016/j.xcrm.2020.100140

Cited by 72 publications

(52 citation statements)

References 49 publications

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“…Intriguingly, increased levels of SPP1 were associated with more favorable outcomes in IPF, in contrast to the rest of the ILDs. Circulating OPN was recently associated with immune complexes-driven profibrotic macrophage activity in SSc-ILD ( 55 ) and it could be speculated that OPN plays a more significant role in autoimmune-driven fibrosis as compared to IPF. Furthermore, recent studies with models of tissue repair and scar formation following heart injury showed that osteopontin expressing recruited macrophage populations play both a pro-fibrotic and pro-resolving role ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

Collagen 1a1 Expression by Airway Macrophages Increases In Fibrotic ILDs and Is Associated With FVC Decline and Increased Mortality

et al. 2021

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Within the Interstitial Lung Diseases (ILD), patients with idiopathic pulmonary fibrosis (IPF) and a subset of those with non-IPF fibrotic ILD have a distinct clinical phenotype of progression despite management. This group of patients has been collectively termed the progressive fibrotic phenotype (PFP). Their early recognition may facilitate access to antifibrotic therapies to prevent or slow progression. Macrophages/monocytes within the lung orchestrate the progression and maintenance of fibrosis. A novel role for monocyte-derived macrophages during tissue damage and wound healing is the expression of collagens. We examined Collagen 1a1 expression in airway macrophages from ILD patients at diagnosis. COL1A1 mRNA levels from BAL cells were elevated in IPF and Non-IPF patients. The presence of a UIP pattern and a subsequent progressive phenotype were significantly associated with the higher BAL COL1A1 levels. In Non-IPF patients, higher COL1A1 levels were associated with a more than twofold increase in mortality. The intracellular localisation of COL1A1 in airway macrophages was demonstrated by confocal microscopy in CD45 and CD163 co-staining assays. Additionally, airway macrophages co-expressed COL1A1 with the profibrotic SPP1 gene product osteopontin. The levels of SPP1 mRNA and OPN in the BAL were significantly higher in IPF and Non-IPF patients relative to healthy. Our results suggest that profibrotic airway macrophages are increased in the BAL of patients with IPF and other ILDs and co-express COL1A1 and OPN. Importantly, COL1A1 expression by pro-fibrotic airway macrophages could be a marker of disease progression and poor survival in ILDs.

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Section: Discussionmentioning

confidence: 99%

Collagen 1a1 Expression by Airway Macrophages Increases In Fibrotic ILDs and Is Associated With FVC Decline and Increased Mortality

et al. 2021

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“…58 A recent paper with IPF shows that Spp1 is primarily expressed in myeloid cells in interstitial pulmonary fibrosis and IL-6 stimulates OPN expression in macrophages, which sensitizes and mobilizes fibroblasts toward other fibrogenic growth factors. 59 Accordingly, it is likely that one major outcome of SPP1 deficiency is altered immune cell type distribution and activation, which possibility will be addressed in future studies.…”

Section: Discussionmentioning

confidence: 99%

Osteopontin deficiency leads to the resolution of prostatic fibrosis and inflammation

Popovics

Jain

Skalitzky

et al. 2021

Preprint

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Fibrogenic and inflammatory processes in the prostate are linked to the development of lower urinary tract symptoms (LUTS) in men. Our previous studies identified that osteopontin (OPN), a pro-fibrotic cytokine, is abundant in the prostate of men with LUTS and its secretion is stimulated by inflammatory cytokines potentially to drive fibrosis. This study investigates whether the lack of OPN ameliorates inflammation and fibrosis in the mouse prostate. We instilled uropathogenic E. coli (UTI89) or saline (control) transurethrally to C57BL/6J (WT) or Spp1tm1Blh/J (OPN-KO) mice and collected the prostates one or 8 weeks later. We found that OPN mRNA and protein expression were significantly induced by E. coli-instillation in the dorsal prostate (DP) after one week in WT mice. Deficiency in OPN expression led to decreased inflammation and fibrosis and the prevention of urinary dysfunction after 8 weeks. RNAseq analysis identified that E. coli-instilled WT mice expressed increased levels of inflammatory and fibrotic marker RNAs compared to OPN-KO mice including Col3a1, Dpt, Lum and Mmp3 which were confirmed by RNAscope. Our results indicate that OPN is induced by inflammation and prolongs the inflammatory state; genetic blockade of OPN accelerates recovery after inflammation, including a resolution of prostate fibrosis.

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“…Gene expression of bulk scleroderma specimens of skin often does not reveal up-regulation of AREG in the diseased biopsies although a recent report showed up-regulation in scleroderma patients [ 41 ]. However, activated immune cells from scleroderma show a high level of Areg expression [ 42 ], indicating that expression of AREG is associated with specific cell types in the disease process, rather than the overall gene expression. Indeed, single cell analyses indicate that AREG is highly expressed in myofibroblasts, not other types of fibroblasts in scleroderma patients [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

A critical role of AREG for bleomycin-induced skin fibrosis

et al. 2021

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We report our discovery of an important player in the development of skin fibrosis, a hallmark of scleroderma. Scleroderma is a fibrotic disease, affecting 70,000 to 150,000 Americans. Fibrosis is a pathological wound healing process that produces an excessive extracellular matrix to interfere with normal organ function. Fibrosis contributes to nearly half of human mortality. Scleroderma has heterogeneous phenotypes, unpredictable outcomes, no validated biomarkers, and no effective treatment. Thus, strategies to slow down scleroderma progression represent an urgent medical need. While a pathological wound healing process like fibrosis leaves scars and weakens organ function, oral mucosa wound healing is a scarless process. After re-analyses of gene expression datasets from oral mucosa wound healing and skin fibrosis, we discovered that several pathways constitutively activated in skin fibrosis are transiently induced during oral mucosa wound healing process, particularly the amphiregulin (Areg) gene. Areg expression is upregulated ~ 10 folds 24hrs after oral mucosa wound but reduced to the basal level 3 days later. During bleomycin-induced skin fibrosis, a commonly used mouse model for skin fibrosis, Areg is up-regulated throughout the fibrogenesis and is associated with elevated cell proliferation in the dermis. To demonstrate the role of Areg for skin fibrosis, we used mice with Areg knockout, and found that Areg deficiency essentially prevents bleomycin-induced skin fibrosis. We further determined that bleomycin-induced cell proliferation in the dermis was not observed in the Areg null mice. Furthermore, we found that inhibiting MEK, a downstream signaling effector of Areg, by selumetinib also effectively blocked bleomycin-based skin fibrosis model. Based on these results, we concluded that the Areg-EGFR-MEK signaling axis is critical for skin fibrosis development. Blocking this signaling axis may be effective in treating scleroderma.

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Osteopontin Links Myeloid Activation and Disease Progression in Systemic Sclerosis

Cited by 72 publications

References 49 publications

Collagen 1a1 Expression by Airway Macrophages Increases In Fibrotic ILDs and Is Associated With FVC Decline and Increased Mortality

Collagen 1a1 Expression by Airway Macrophages Increases In Fibrotic ILDs and Is Associated With FVC Decline and Increased Mortality

Osteopontin deficiency leads to the resolution of prostatic fibrosis and inflammation

A critical role of AREG for bleomycin-induced skin fibrosis

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