STAT3 Gain of Function: A New Kid on the Block in Interstitial Lung Diseases

Fabre, Alexandre; Marchal, Sarah; Forbes, Lisa R.; Vogel, Tiphanie P.; Barlogis, Vincent; Triolo, Valérie; Rohrlich, Pierre‐Simon; Bérard, Étienne; Frankel, Diane; Ambrosetti, Damien; Soler, Christine; Hoflack, Marie; Baque, Marie; Bosdure, E.; Baravalle, Mélisande; Carsin, A.; Dubus, Jean‐Christophe; Giovannini‐Chami, Lisa

doi:10.1164/rccm.201707-1500im

Cited by 22 publications

(34 citation statements)

References 5 publications

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“…As for PID associated ILD, it has been recognized that PID may be associated with immune-mediated ILD especially in auto-inflammatory disorders, diseases of immune dysregulation, and predominantly antibody deficiencies such as CVID [11][12][13][14][15][16][17][18][19][20]. Two new auto-inflammatory disorders SAVI and COPA syndrome which has been reported to be associated with ILD [15][16][17] were both found in our study cohort.…”

Section: Discussionsupporting

confidence: 50%

Etiologic spectrum of interstitial lung diseases in Chinese children older than 2 years of age

Tang

Liu

et al. 2020

Orphanet J Rare Dis

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Background: Childhood interstitial lung diseases (ILD) (chILD) refer to a rare heterogeneous group of disorders. Global collaborations have been working on the etiologies and classification scheme of chILD. With the development of medical technologies, some new diseases were identified to be associated with chILD and its etiologic spectrum is expanding. The aim of this study is to describe the etiologic spectrum of chILD in children older than 2 years of age and summarize the approaches to diagnosis of chILD. Methods: We made a retrospective analysis of children older than 2 years of age with chILD who referred to Beijing Children's Hospital from 21 provinces all over China from 2013 to 2018. After excluding pulmonary infection, congenital heart disease, bronchopulmonary dysplasia, bronchiolitis obliterans and bronchiectasis, 133 patients were included and categorized by etiology. Clinical manifestations, high-resolution computed tomography, laboratory data, genetic data and pathologic findings were all collected and reviewed. Results: Systemic disease associated ILD were the most common causes, accounting for 49.6% of the patients, followed by alveolar structure disorder-associated ILD (27%), exposure related ILD (13.5%), and disorders masquerading as ILD (3.8%). In systemic disease associated ILD, in addition to common etiologies such as vasculitis (10.5%) and connective tissue diseases (9.0%), primary immunodeficiency diseases (PID) associated ILD (9.8%), interstitial pneumonia with autoimmune features (6.8%), and metabolic diseases (6.8%) were not rarely found. Some newly reported etiologies such as STING-associated vasculopathy with onset in infancy, COPA syndrome and STAT3 mutation were included in PID associated ILD. Genetic tests contributed to 15% of the diagnoses which mainly distributed in PID associated ILD, metabolic diseases and surfactant dysfunction disorders, and contributed to the final diagnoses more than lung biopsies (13.5%) and biopsies of rashes or other tissues (12%). Conclusions: This study first demonstrated an etiologic spectrum of chILD in Chinese children older than 2 years of age and summarized the approaches to diagnosis. The etiologic spectrum of chILD is expanding with more genetic etiologies being recognized.

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Section: Discussionsupporting

confidence: 50%

Etiologic spectrum of interstitial lung diseases in Chinese children older than 2 years of age

Tang

Liu

et al. 2020

Orphanet J Rare Dis

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“…Association between STAT3 and the onset of senescence are well documented (reviewed in (47)) and STAT3 activity is strongly associated with interstitial lung diseases such as IPF (35,(48)(49)(50). In this study, we identified STAT3 as playing a key role in the shift of secretory profile, cell cycle arrest, and mitochondrial respiration.…”

Section: Discussionmentioning

confidence: 74%

STAT3 Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts

Waters

Blokland

Pathinayake

et al. 2019

Am J Respir Cell Mol Biol

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Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown cause with a median survival of only 3 years. We and others have shown that fibroblasts derived from IPF-lungs display characteristics of senescent cells and that dysregulated activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) correlates with IPF progression. The question of whether STAT3 activation is involved in fibroblast senescence remains unanswered. We hypothesized that inhibiting STAT3 activation after oxidant-induced senescence would attenuate characteristics of the senescent phenotype. We aimed to characterize a model of oxidant induced senescence in human lung fibroblasts and to determine the effect of inhibiting STAT3 activity on the development of senescence. Exposing human lung fibroblasts to 150µM hydrogen peroxide (H 2 O 2) resulted in increased senescenceassociated-β-galactosidase (SA-β-Gal) content, expression of p21 and interleukin (IL)-6, all of which are features of senescence. The shift into senescence was accompanied by an increase of STAT3 translocation to the nucleus and mitochondria. Additionally, Seahorse analysis provided evidence of increased mitochondrial respiration characterized by increased basal respiration, proton leak and an associated increase in superoxide (O 2-) production in senescent fibroblasts. Targeting STAT3 activity using the small molecule inhibitor STA-21 attenuated IL-6 production, reduced p21 levels, decreased SA-β-Gal accumulation and restored normal mitochondrial function. The results of this study illustrate that stress-induced senescence in lung fibroblasts involves the activation of STAT3 which can be pharmacologically modulated.

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“…Patients with germline STAT3 GOF mutations have been associated with early-onset multiorgan autoimmunity, lymphoproliferation, early-onset growth failure, and may have severe recurrent infections. Studies have also shown an association of STAT3 GOF with interstitial pneumonitis and role of STAT3 signaling in interstitial and fibrotic lung disease pathogenesis 14…”

Section: Introductionmentioning

confidence: 97%

<p>Genetics of COPA syndrome</p>

Kumrah

Mathew

Vignesh

et al. 2019

TACG

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Inborn errors of immunity usually not only result in immunodeficiency but may also manifest as immune dysregulation in the form of autoinflammation, autoimmunity, or sometimes malignancy. One of the most recently discovered monogenic disorder of immune dysregulation is COPA syndrome. COPA syndrome is an inherited autoimmune disorder caused by mutations in COPA gene. COPA gene encodes for α subunit of the COP1 protein, which is involved in the reverse vesicular protein transport from Golgi apparatus to the endoplasmic reticulum (ER). The inheritance pattern of COPA syndrome is autosomal dominant, and the patients typically present with interstitial lung disease with pulmonary hemorrhage and subsequently develop arthritis. Immunological features involve autoantibody formation, elevated expression of IL-1β and IL-6, and increase in the number of Th17 cells. Molecular pathophysiology of COPA syndrome is not clearly understood. However, it is known that accumulation of unfolded proteins in ER leads to ER stress, which is an indirect result of aberrant vesicular transport of proteins from Golgi apparatus to ER and defective cellular autophagy. ER stress induces inflammation and is responsible for pathogenesis of a large number of chronic inflammatory diseases. Unfolded protein response process responds to improperly folded proteins and defends against stress in ER to ensure the fidelity of the protein folding. It maintains the expression of stress-response genes and causes initiation of inflammatory signaling pathways essential for the innate immunity. Mutation in COPA gene associated with defective protein sorting to ER has unearthed a new primary immunodeficiency disease with a unique clinical phenotype. This review highlights the clinical and molecular aspects of COPA syndrome.

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STAT3 Gain of Function: A New Kid on the Block in Interstitial Lung Diseases

Cited by 22 publications

References 5 publications

Etiologic spectrum of interstitial lung diseases in Chinese children older than 2 years of age

Etiologic spectrum of interstitial lung diseases in Chinese children older than 2 years of age

STAT3 Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts

<p>Genetics of COPA syndrome</p>

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