c-Jun N-terminal kinase (JNK)–mediated induction of mSin1 expression and mTORC2 activation in mesenchymal cells during fibrosis

Walker, Neff; Mazzoni, Serina M.; Vittal, Ragini; Fingar, Diane C.; Lama, Vibha N.

doi:10.1074/jbc.ra118.003926

Cited by 11 publications

(4 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, HDG decreases BLM-associated collagen deposition by lowering the levels of alpha-smooth muscle actin, type I collagen, inflammatory cytokines TNF-α and IL6, TGF-β1, and connective tissue growth factor [ 90 ]. Further analysis of the mechanism showed the ability of HDG to block Ras/JNK/NFAT4 signal transduction, which controls type I collagen expression in mesenchymal cells during lung fibrosis formation [ 91 ]. These mechanisms set the stage for a trial proposed to assess the efficacy of FZHY against post-COVID fibrosis in combination with pulmonary rehabilitation and vitamin C intake [ 46 ].…”

Section: Clinical Trials Of Therapies For Post-covid Lung Fibrosismentioning

confidence: 99%

Lung Fibrosis after COVID-19: Treatment Prospects

et al. 2021

View full text Add to dashboard Cite

At the end of 2019, a highly contagious infection began its ominous conquest of the world. It was soon discovered that the disease was caused by a novel coronavirus designated as SARS-CoV-2, and the disease was thus abbreviated to COVID-19 (COVID). The global medical community has directed its efforts not only to find effective therapies against the deadly pathogen but also to combat the concomitant complications. Two of the most common respiratory manifestations of COVID are a significant reduction in the diffusing capacity of the lungs (DLCO) and the associated pulmonary interstitial damage. One year after moderate COVID, the incidence rate of impaired DLCO and persistent lung damage still exceeds 30%, and one-third of the patients have severe DLCO impairment and fibrotic lung damage. The persistent respiratory complications may cause substantial population morbidity, long-term disability, and even death due to the lung fibrosis progression. The incidence of COVID-induced pulmonary fibrosis caused by COVID can be estimated based on a 15-year observational study of lung pathology after SARS. Most SARS patients with fibrotic lung damage recovered within the first year and then remained healthy; however, in 20% of the cases, significant fibrosis progression was found in 5–10 years. Based on these data, the incidence rate of post-COVID lung fibrosis can be estimated at 2–6% after moderate illness. What is worse, there are reasons to believe that fibrosis may become one of the major long-term complications of COVID, even in asymptomatic individuals. Currently, despite the best efforts of the global medical community, there are no treatments for COVID-induced pulmonary fibrosis. In this review, we analyze the latest data from ongoing clinical trials aimed at treating post-COVID lung fibrosis and analyze the rationale for the current drug candidates. We discuss the use of antifibrotic therapy for idiopathic pulmonary fibrosis, the IN01 vaccine, glucocorticosteroids as well as the stromal vascular fraction for the treatment and rehabilitation of patients with COVID-associated pulmonary damage.

show abstract

Section: Clinical Trials Of Therapies For Post-covid Lung Fibrosismentioning

confidence: 99%

Lung Fibrosis after COVID-19: Treatment Prospects

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Consistent with this clinical observation, prior mechanistic studies demonstrate that CLAD is associated with an increase in allo‐reactive CD4+ T cells 4,5 and mononuclear phagocytic cells (i.e., monocytes and macrophages) 6,7 . Our prior research has shown that donor‐derived mesenchymal stromal cells (MCs) within CLAD allografts have upregulation of autocrine lysophosphatidic acid(LPA)–autotaxin(ATX) autocrine signaling, 8 elevated cap‐dependent translation 9 and resistance to molecular target of rapamycin (mTOR) inhibitors 10 . This abnormal signaling results in increased proliferation, mobilization, and fibrotic gene expression 8,11,12 .…”

Section: Introductionmentioning

confidence: 53%

“…macrophages). 6,7 Our prior research has shown that donor-derived mesenchymal stromal cells (MCs) within CLAD allografts have upregulation of autocrine lysophosphatidic acid(LPA)-autotaxin(ATX) autocrine signaling, 8 elevated cap-dependent translation 9 and resistance to molecular target of rapamycin (mTOR) inhibitors. 10 This abnormal signaling results in increased proliferation, mobilization, and fibrotic gene expression.…”

mentioning

confidence: 99%

Interleukin 6 trans-signaling is a critical driver of lung allograft fibrosis

Wheeler

Misumi

Walker

et al. 2021

American Journal of Transplantation

Self Cite

View full text Add to dashboard Cite

Histopathologic examination of lungs afflicted by chronic lung allograft dysfunction (CLAD) consistently shows both mononuclear cell (MNC) inflammation and mesenchymal cell (MC) fibroproliferation. We hypothesize that interleukin 6 (IL‐6) trans‐signaling may be a critical mediator of MNC‐MC crosstalk and necessary for the pathogenesis of CLAD. Bronchoalveolar lavage (BAL) fluid obtained after the diagnosis of CLAD has approximately twofold higher IL‐6 and soluble IL‐6 receptor (sIL‐6R) levels compared to matched pre‐CLAD samples. Human BAL‐derived MCs do not respond to treatment with IL‐6 alone but have rapid and prolonged JAK2‐mediated STAT3 Tyr705 phosphorylation when exposed to the combination of IL‐6 and sIL‐6R. STAT3 phosphorylation within MCs upregulates numerous genes causing increased invasion and fibrotic differentiation. MNC, a key source of both IL‐6 and sIL‐6R, produce minimal amounts of these proteins at baseline but significantly upregulate production when cocultured with MCs. Finally, the use of an IL‐6 deficient recipient in a murine orthotopic transplant model of CLAD reduces allograft fibrosis by over 50%. Taken together these results support a mechanism where infiltrating MNCs are stimulated by resident MCs to release large quantities of IL‐6 and sIL‐6R which then feedback onto the MCs to increase invasion and fibrotic differentiation.

show abstract

“…However, the relationship is probably more complex since it has also been shown that JNK promotes mTORC2 signaling. In mesenchymal cells (MCs), JNK prevents the proteasomal degradation of SIN1 during LPA stimulation, thus promoting mTORC2 activation [ 351 ]. The JNK/mTORC2 signaling is required during the fibrotic activation of MCs.…”

Section: Cross-talk With Other Pathwaysmentioning

confidence: 99%

The mTORC2 signaling network: targets and cross-talks

Ragupathi,

Kim,

Jacinto

2024

Biochemical Journal

View full text Add to dashboard Cite

The mechanistic target of rapamycin, mTOR, controls cell metabolism in response to growth signals and stress stimuli. The cellular functions of mTOR are mediated by two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. Rapamycin and its analogs are currently used in the clinic to treat a variety of diseases and have been instrumental in delineating the functions of its direct target, mTORC1. Despite the lack of a specific mTORC2 inhibitor, genetic studies that disrupt mTORC2 expression unravel the functions of this more elusive mTOR complex. Like mTORC1 which responds to growth signals, mTORC2 is also activated by anabolic signals but is additionally triggered by stress. mTORC2 mediates signals from growth factor receptors and G-protein coupled receptors. How stress conditions such as nutrient limitation modulate mTORC2 activation to allow metabolic reprogramming and ensure cell survival remains poorly understood. A variety of downstream effectors of mTORC2 have been identified but the most well-characterized mTORC2 substrates include Akt, PKC, and SGK, which are members of the AGC protein kinase family. Here, we review how mTORC2 is regulated by cellular stimuli including how compartmentalization and modulation of complex components affect mTORC2 signaling. We elaborate on how phosphorylation of its substrates, particularly the AGC kinases, mediates its diverse functions in growth, proliferation, survival, and differentiation. We discuss other signaling and metabolic components that cross-talk with mTORC2 and the cellular output of these signals. Lastly, we consider how to more effectively target the mTORC2 pathway to treat diseases that have deregulated mTOR signaling.

show abstract

c-Jun N-terminal kinase (JNK)–mediated induction of mSin1 expression and mTORC2 activation in mesenchymal cells during fibrosis

Cited by 11 publications

References 51 publications

Lung Fibrosis after COVID-19: Treatment Prospects

Lung Fibrosis after COVID-19: Treatment Prospects

Interleukin 6 trans-signaling is a critical driver of lung allograft fibrosis

The mTORC2 signaling network: targets and cross-talks

Contact Info

Product

Resources

About