Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury

Leaf, Irina A.; Nakagawa, Shoichi; Johnson, Bryce G.; Joo, Jin; Mittelsteadt, Kristen; Guckian, Kevin M.; Gomez, Ivan G.; Altemeier, William A.; Duffield, Jeremy S.

doi:10.1172/jci87532

Cited by 124 publications

(103 citation statements)

References 58 publications

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“…Informed permission for the use of fetal tissues was obtained from all patients. The isolation of cells was approved by the University of Washington Institutional Review Board (IRB447773EA) and performed at the University of Washington Medical Center as previously described (81). Details of the materials and methods for this study can be found in SI Appendix, SI Materials & Methods.…”

Section: Methodsmentioning

confidence: 99%

Three-dimensional biomimetic vascular model reveals a RhoA, Rac1, and N -cadherin balance in mural cell–endothelial cell-regulated barrier function

Alimperti

Mirabella

Bajaj

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The integrity of the endothelial barrier between circulating blood and tissue is important for blood vessel function and, ultimately, for organ homeostasis. Here, we developed a vessel-on-a-chip with perfused endothelialized channels lined with human bone marrow stromal cells, which adopt a mural cell-like phenotype that recapitulates barrier function of the vasculature. In this model, barrier function is compromised upon exposure to inflammatory factors such as LPS, thrombin, and TNFα, as has been observed in vivo. Interestingly, we observed a rapid physical withdrawal of mural cells from the endothelium that was accompanied by an inhibition of endogenous Rac1 activity and increase in RhoA activity in the mural cells themselves upon inflammation. Using a system to chemically induce activity in exogenously expressed Rac1 or RhoA within minutes of stimulation, we demonstrated RhoA activation induced loss of mural cell coverage on the endothelium and reduced endothelial barrier function, and this effect was abrogated when Rac1 was simultaneously activated. We further showed that N-cadherin expression in mural cells plays a key role in barrier function, as CRISPRmediated knockout of N-cadherin in the mural cells led to loss of barrier function, and overexpression of N-cadherin in CHO cells promoted barrier function. In summary, this bicellular model demonstrates the continuous and rapid modulation of adhesive interactions between endothelial and mural cells and its impact on vascular barrier function and highlights an in vitro platform to study the biology of perivascular-endothelial interactions.

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Section: Methodsmentioning

confidence: 99%

Three-dimensional biomimetic vascular model reveals a RhoA, Rac1, and N -cadherin balance in mural cell–endothelial cell-regulated barrier function

Alimperti

Mirabella

Bajaj

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Indeed, our mining of RNAseq datasets from lung fibroblasts derived from slow and rapid progressing IPF patient lung samples, and normal lung samples supports an expansion of a PDGFRß- and PDGFRα-expressing stromal population in IPF. Further, various studies have suggested that pericytes express higher levels of innate immune microbial sensors[13, 88] and IPF lung fibroblasts, notably from progressive IPF patients, express TLR9[78, 79] and TLR4[77], and the activation of these microbial sensors leads to myofibroblast differentiation[77–79]. Together, these studies suggest that pericyte-derived fibroblasts and myofibroblasts are present in IPF, and these cells might contribute to fibrotic progression through various mechanisms including microbial sensing pathways.…”

Section: Evidence For the Expansion Of Pericyte-derived Fibroblasts Amentioning

confidence: 99%

Heterogeneity of Fibroblasts and Myofibroblasts in Pulmonary Fibrosis

Habiel

Hogaboam

2017

Curr Pathobiol Rep

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Purpose of review Idiopathic Pulmonary Fibrosis (IPF) is the most common form of interstitial lung diseases of unknown eathiopathogenesis, mean survival of 3-5 years and limited therapeutics. Characterized by a loss of alveolar type II epithelial cells and aberrant activation of stromal cells, considerable effort was undertaken to characterize the origin and activation mechanisms of fibroblasts and myofibroblasts in IPF lungs. In this review, the origin and contribution of fibroblast and myofibroblasts in lung fibrosis will be summarized. Recent findings Lineage tracing experiments suggested that interstitial lung fibroblasts and lipofibroblasts, pericytes and mesothelial cells differentiate into myofibroblasts. However, epithelial and bone marrow derived cells may give rise to collagen expressing fibroblasts but do not differentiate into myofibroblasts. Summary There is great heterogeneity in fibroblasts and myofibroblasts in fibrotic lungs. Further, there is evidence for the expansion of pericyte derived myofibroblasts and loss of lipofibroblasts and lipofibroblast derived myofibroblasts in IPF.

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“…58 In addition, myofibroblast activation is also accompanied by innate immune system, partially through the secretion and expression of pro-inflammatory cytokines. 17,59 Among the pro-inflammatory cytokines and growth factors, IL-1β, IL-6, and TGF-β1 are the typical factors, released by leukocytes that traffic to the damaged kidney tissue. 60,61 These inflammatory cytokines induce the activation of fibroblasts, which are strong producers of the ECM component.…”

Section: Discussionmentioning

confidence: 99%

Anti‐fibrotic effects of synthetic TGF‐β1 and Smad oligodeoxynucleotide on kidney fibrosis in vivo and in vitro through inhibition of both epithelial dedifferentiation and endothelial‐mesenchymal transitions

Gwon

Kim

et al. 2019

The FASEB Journal

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Kidney fibrosis is a common process of various kidney diseases leading to end-stage renal failure irrespective of etiology. Myofibroblasts are crucial mediators in kidney fibrosis through production of extracellular matrix (ECM), but their origin has not been clearly identified. Many study proposed that epithelial and endothelial cells become myofibroblasts by epithelial dedifferentiation and endothelial-mesenchymal transition (EndoMT). TGF-β1/Smad signaling plays a crucial role in partly epithelial-mensencymal transition (EMT) and EndoMT. Thus, we designed the TGF-β1/ Smad oligodeoxynucleotide (ODN), a synthetic short DNA containing complementary sequence for Smad transcription factor and TGF-β1 mRNA. Therefore, this study investigated the anti-fibrotic effect of synthetic TGF-β1/Smad ODN on UUO-induced kidney fibrosis in vivo model and TGF-β1-induced in vitro model.To examine the effect of TGF-β1/Smad ODN, we performed various experiments to evaluate kidney fibrosis. The results showed that UUO induced inflammation, ECM accumulation, epithelial dedifferentiation and EndoMT processes, and tubular atrophy. However, synthetic TGF-β1/Smad ODN significantly suppressed UUOinduced fibrosis. Furthermore, synthetic ODN attenuated TGF-β1-induced epithelial dedifferentiation and EndoMT program via blocking TGF-β1/Smad signaling. In conclusion, this study demonstrated that administration of synthetic TGF-β1/Smad ODN attenuates kidney fibrosis, epithelial dedifferentiation, and EndoMT processes.The findings propose the possibility of synthetic ODN as a new effective therapeutic tool for kidney fibrosis. K E Y W O R D SEndoMT, epithelial dedifferentiation, kidney fibrosis, TGF-β1/Smad oligodeoxynucleotide, UUO 334 | GWON et al. | MATERIALS AND METHODS | Synthesis of oligodeoxynucleotidesTarget site of TGF-β1 was selected using S-Fold program. Synthetic ODNs were synthesized on Macrogen (Seoul, Korea). TGF-β1/Smad ODN and scrambled (Scr) ODN 340 | GWON et al. F I G U R E 3 TGF-β1/Smad ODN attenuated kidney fibrosis and ECM accumulation in UUO-injured mice. A, Pathological stain withhematoxylin and eosin (H&E) and B, Masson's trichrome performed using kidney sections. Trichrome stain showed that TGF-β1/Smad ODN attenuated interstitial fibrosis. C, The quantitative analysis of blue-stained collagen in trichrome staining (n = 3). D, Collagen Ⅰ was detected by RT-PCR. This result demonstrated the effect of synthetic ODN on ECM accumulation. The graphs summarize the analysis of the Collagen Ⅰ mRNA expressions (n = 4). E, Immunohistochemistry stain showed that the expression of fibronectin was inhibited by TGF-β1/Smad ODN administration in UUO-injured mice. F, The quantitative graph of fibronectin expression. G, Representative Western blot data revealed that TGF-β1/Smad ODN diminished expression of fibronectin. β-actin was used to confirm equal volume protein sample loading (n = 3). Scale bar = 50 μm; +: treated; −: un-treated; *P < .05 compared to the normal control group; †P < .05 compared to the UUO group

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Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury

Cited by 124 publications

References 58 publications

Three-dimensional biomimetic vascular model reveals a RhoA, Rac1, and N -cadherin balance in mural cell–endothelial cell-regulated barrier function

Three-dimensional biomimetic vascular model reveals a RhoA, Rac1, and N -cadherin balance in mural cell–endothelial cell-regulated barrier function

Heterogeneity of Fibroblasts and Myofibroblasts in Pulmonary Fibrosis

Anti‐fibrotic effects of synthetic TGF‐β1 and Smad oligodeoxynucleotide on kidney fibrosis in vivo and in vitro through inhibition of both epithelial dedifferentiation and endothelial‐mesenchymal transitions

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