Combined anti-fibrotic and anti-inflammatory properties of JAK-inhibitors on macrophages in vitro and in vivo: Perspectives for scleroderma-associated interstitial lung disease

Lescoat, Alain; Lelong, M; Jeljeli, Mohamed; Piquet‐Pellorce, Claire; Morzadec, Claudie; Ballerie, Alice; Jouneau, S.; Jégo, Patrick; Vernhet, Laurent; Batteux, Frédéric; Fardel, Olivier; Lecureur, Valérie

doi:10.1016/j.bcp.2020.114103

Cited by 102 publications

(90 citation statements)

References 67 publications

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“…This pathway is dysregulated in obesity and metabolic diseases [ 75 ]. A recent study reported the use of JAK inhibitors on pathologies with lung fibrosis involvement showing that JAK/STAT plays a role in the development of fibrosis [ 76 ]. Moreover, other studies highlight lung fibrotic stability after the administration of JAK inhibitors such as Baricitinib in patients with rheumatoid arthritis and lung involvement [ 77 ].…”

Section: Onset Of Fibrosis: the Contribution Of Dysregulated Lipidmentioning

confidence: 99%

Metabolic Dysregulation in Idiopathic Pulmonary Fibrosis

Bargagli

Refini

d’Alessandro

et al. 2020

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative disorder limited to the lung. New findings, starting from our proteomics studies on IPF, suggest that systemic involvement with altered molecular mechanisms and metabolic disorder is an underlying cause of fibrosis. The role of metabolic dysregulation in the pathogenesis of IPF has not been extensively studied, despite a recent surge of interest. In particular, our studies on bronchoalveolar lavage fluid have shown that the renin–angiotensin–aldosterone system (RAAS), the hypoxia/oxidative stress response, and changes in iron and lipid metabolism are involved in onset of IPF. These processes appear to interact in an intricate manner and to be related to different fibrosing pathologies not directly linked to the lung environment. The disordered metabolism of carbohydrates, lipids, proteins and hormones has been documented in lung, liver, and kidney fibrosis. Correcting these metabolic alterations may offer a new strategy for treating fibrosis. This paper focuses on the role of metabolic dysregulation in the pathogenesis of IPF and is a continuation of our previous studies, investigating metabolic dysregulation as a new target for fibrosis therapy.

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Section: Onset Of Fibrosis: the Contribution Of Dysregulated Lipidmentioning

confidence: 99%

Metabolic Dysregulation in Idiopathic Pulmonary Fibrosis

Bargagli

Refini

d’Alessandro

et al. 2020

IJMS

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“…LPS binds to the TLR4 macrophage membrane receptor, to trigger the differentiation of M1 phenotype macrophages involved in pro-inflammatory responses and the production of pro-inflammatory related factors through the activation of intracellular signaling cascades, including the mitogen-activated protein kinase (MAPK), 8 nuclear factor kappa-B (NF-κB), 6 , 8 Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways. 9 Activated macrophages are usually divided into two categories, M1-like and M2-like macrophages. 10 The M1 differentiation of macrophages is enhanced in the early stage of sepsis, probably due to stimulation by cytokines, including interferon-γ (IFN-γ) and granulocyte macrophage colony stimulating factor (GM-CSF), and exogenous bacterial toxins, such as LPS.…”

Section: Introductionmentioning

confidence: 99%

The ACE2-Ang-(1‑7)-Mas Axis Modulates M1/M2 Macrophage Polarization to Relieve CLP-Induced Inflammation via TLR4-Mediated NF-кb and MAPK Pathways

Pan¹,

Huang²,

Wang³

et al. 2021

JIR

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has been identified as an important anti-inflammatory and anti-fibrotic factor. This study determined how the ACE2-Ang-(1-7)-Mas axis affected M1/ M2 macrophage polarization and thus contributed to anti-inflammatory processes in the cecal ligation and puncture (CLP)-induced inflammation model. Materials and Methods: ELISA, western blotting, and qRT-PCR were used to verify that Ang-(1-7) decreased the expression of pro-inflammatory cytokines and increased anti-inflammatory cytokines. The differentiation of M1/M2 macrophages was assessed by flow cytometry for assessing the cell-surface markers, CD86 and CD206. The related key receptors and pathways were analyzed by Western blotting, qRT-PCR, and immunofluorescence. CLP-induced inflammatory mice models were used for in vivo studies. Hematoxylin and eosin and immunohistochemical and immunofluorescence staining protocols were used to analyze histological changes in the spleen, and the related key pathway proteins were analyzed by western blotting. Results: Ang-(1-7) decreased the expressions of the TNF-α and IL-6 pro-inflammatory cytokines and increased the expressions of the IL-4 and IL-10 anti-inflammatory cytokines. INOS and TNFα, which represented M1 macrophage polarization, were decreased by Ang-(1-7). ARG1 and CD163, which represented M2 macrophage polarization, were increased by Ang-(1-7). Both Mas receptor and ACE2 are expressed on macrophages. Furthermore, the ACE2-Ang-(1-7)-MAS axis modulated macrophage polarization by ameliorating TLR4 expression and regulating the NF-кB and MAPK pathways. In addition, splenomegaly and macrophage infiltration were observed in the spleen of the CLP-induced mouse models and macrophages in the spleen suspension of CLP models were shifted to M1 phenotype and were effectively inhibited by Ang-(1-7) via the TLR4mediated NF-кB and MAPK pathways, which could be partially rescued by A-779. Ang-(1-7) inhibited inflammatory responses in vivo and in vitro, and repressed macrophage polarization toward the M1 phenotype and promoted it toward the M2 phenotype, which provided new evidence for the anti-inflammation activity of the ACE2-Ang -(1-7)-MAS axis. Conclusion:

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“…Tofacitinib is a “ pan JAK inhibitor” as it has a low JAK selectivity being able to block JAK1, JAK2, and JAK3 [ 31 ]. Some major mediators which are deemed fundamental in SSc pathogenesis are indeed involved in JAK/STAT signalling pathway: IL-6, IFN type 1 and 2 and most importantly IL-4 and IL-13 [ 32 ]. Moreover, different mouse models of SSc showed a potent anti-fibrotic effect for tofacitinib [ 30 ].…”

Section: Resultsmentioning

confidence: 99%

An update on targeted therapies in systemic sclerosis based on a systematic review from the last 3 years

Campochiaro

Allanore

2021

Arthritis Res Ther

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New molecular mechanisms that can be targeted with specific drugs have recently emerged for the treatment of systemic sclerosis (SSc) patients. Over the past 3 years, the achievement of one large phase 3 trial has led to the approval by drug agencies of the first drug licenced for SSc-related interstitial lung disease. Given this exciting time in the SSc field, we aimed to perform a systemic literature review of phase 1, phase 2 and phase 3 clinical trials and large observational studies about targeted therapies in SSc. We searched MEDLINE/PubMed, EMBASE, and ClinicalTrials.gov for clinical studies from 2016 with targeted therapies as the primary treatment in patients with SSc for skin or lung involvement as the primary clinical outcome measure. Details on the study characteristics, the trial drug used, the molecular target engaged by the trial drug, the inclusion criteria of the study, the treatment dose, the possibility of concomitant immunosuppression, the endpoints of the study, the duration of the study and the results obtained were reviewed. Of the 973 references identified, 21 (4 conference abstracts and 17 articles) were included in the systematic review. A total of 15 phase 1/phase 2 clinical trials, 2 phase 3 clinical trials and 2 observation studies were analysed. The drugs studied in phase 1/phase 2 studies included the following: inebilizumab, dabigatran, C-82, pomalidomide, rilonacept, romilkimab, tocilizumab, tofacitinib, pirfenidone, lenabasum, abatacept, belimumab, riociguat, SAR100842 and lanifibranor. All but 3 studies were performed in early diffuse SSc patients with different inclusion criteria, while 3 studies were performed in SSc patients with interstitial lung disease (ILD). Phase 3 clinical trials investigated nintedanib and tocilizumab. Nintedanib was investigated in SSc-ILD patients whereas tocilizumab focused on early diffuse SSc patients with inflammatory features. Two observational studies including > 50 patients with rituximab as the targeted drug were also evaluated. All these studies offer a real hope for SSc patients. The future challenges will be to customize patient-specific therapeutics with the goal to develop precision medicine for SSc.

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Combined anti-fibrotic and anti-inflammatory properties of JAK-inhibitors on macrophages in vitro and in vivo: Perspectives for scleroderma-associated interstitial lung disease

Cited by 102 publications

References 67 publications

Metabolic Dysregulation in Idiopathic Pulmonary Fibrosis

Metabolic Dysregulation in Idiopathic Pulmonary Fibrosis

The ACE2-Ang-(1‑7)-Mas Axis Modulates M1/M2 Macrophage Polarization to Relieve CLP-Induced Inflammation via TLR4-Mediated NF-кb and MAPK Pathways

An update on targeted therapies in systemic sclerosis based on a systematic review from the last 3 years

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