Ruxolitinib Ameliorates Airway Hyperresponsiveness and Lung Inflammation in a Corticosteroid-Resistant Murine Model of Severe Asthma

Subramanian, Hariharan; Hashem, Tanwir; Bahal, Devika; Kammala, Ananth Kumar; Thaxton, Kanedra; Das, Rupali

doi:10.3389/fimmu.2021.786238

Cited by 13 publications

(7 citation statements)

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“…Interestingly, the stimulation of T cell receptor with anti-CD3 antibody can upregulate the expression of SERPINB10 in Th2-polarized cells but has no effect on the expression of SERPINB10 in Th1-polarized cells, proving that it is a stable marker in non-Th2-type asthma ( 51 ). Severe asthma is dominated by Th1/Th17 cytokine responses and rarely has a Th2-mediated immune imbalance ( 52 ), whereas this phenomenon is consistent with our findings. A variety of immune cells associated with SERPINB10, such as neutrophils and dendritic cells, have also been shown to play an important role in asthma through autophagy.…”

Section: Discussionsupporting

confidence: 92%

Autophagy-Related Genes Are Involved in the Progression and Prognosis of Asthma and Regulate the Immune Microenvironment

et al. 2022

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BackgroundAutophagy has been proven to play an important role in the pathogenesis of asthma and the regulation of the airway epithelial immune microenvironment. However, a systematic analysis of the clinical importance of autophagy-related genes (ARGs) regulating the immune microenvironment in patients with asthma remains lacking.MethodsClustering based on the k-means unsupervised clustering method was performed to identify autophagy-related subtypes in asthma. ARG-related diagnostic markers in low-autophagy subtypes were screened, the infiltration of immune cells in the airway epithelium was evaluated by the CIBERSORT, and the correlation between diagnostic markers and infiltrating immune cells was analyzed. On the basis of the expression of ARGs and combined with asthma control, a risk prediction model was established and verified by experiments.ResultsA total of 66 differentially expressed ARGs and 2 subtypes were identified between mild to moderate and severe asthma. Significant differences were observed in asthma control and FEV1 reversibility between the two subtypes, and the low-autophagy subtype was closely associated with severe asthma, energy metabolism, and hormone metabolism. The autophagy gene SERPINB10 was identified as a diagnostic marker and was related to the infiltration of immune cells, such as activated mast cells and neutrophils. Combined with asthma control, a risk prediction model was constructed, the expression of five risk genes was supported by animal experiments, was established for ARGs related to the prediction model.ConclusionAutophagy plays a crucial role in the diversity and complexity of the asthma immune microenvironment and has clinical value in treatment response and prognosis.

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Section: Discussionsupporting

confidence: 92%

Autophagy-Related Genes Are Involved in the Progression and Prognosis of Asthma and Regulate the Immune Microenvironment

et al. 2022

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“…High amounts of neutrophils and the prototype CXCL chemokine, CXCL8, were detected in the tracheal aspirates of patients suffering from acute severe asthma, and these correlated positively with the severity [ 42 ]. Gene transcripts of some of these chemokines (CXCL1, CXCL2, and CXCL5) were found to be upregulated in a mouse model of severe asthma [ 43 ]. Mast cells are also implicated in inflammatory processes, such as those associated with asthma.…”

Section: The Role and Therapeutic Relevance Of CXC Motif Chemokines A...mentioning

confidence: 99%

“…CXCL8 levels were found to be elevated in patients' induced sputum [ 49 ], fuelling speculations about the potential therapeutic benefit of CXCR inhibition in severe asthma. While CXCL1, CXCL2, and CXCL5 gene transcripts were shown to be elevated in a mouse model of severe asthma, treatment with Ruxolitinib, an anti-inflammatory drug and powerful inhibitor of janus kinase 1/2 (JAK1/2), caused the upward spiraling to be reversed [ 43 ]. In an animal model of allergic asthma, tofacitinib, another janus kinase (JAK) inhibitor and immunosuppressant authorized for the treatment of rheumatoid arthritis, was found to lower CXCL1 expression while enhancing immunotherapy efficacy [ 41 , 50 ].…”

Section: The Role and Therapeutic Relevance Of CXC Motif Chemokines A...mentioning

confidence: 99%

CXC Chemokines in the Pathogenesis of Pulmonary Disease and Pharmacological Relevance

Komolafe

Pacurari

2022

International Journal of Inflammation

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Chemokines and their receptors play important roles in the pathophysiology of many diseases by regulating the cellular migration of major inflammatory and immune players. The CXC motif chemokine subfamily is the second largest family, and it is further subdivided into ELR motif CXC (ELR+) and non-ELR motif (ELR-) CXC chemokines, which are effective chemoattractants for neutrophils and lymphocytes/monocytes, respectively. These chemokines and their receptors are expected to have a significant impact on a wide range of lung diseases, many of which have inflammatory or immunological underpinnings. As a result, manipulations of this subfamily of chemokines and their receptors using small molecular agents and other means have been explored for potential therapeutic benefit in the setting of several lung pathologies. Furthermore, encouraging preclinical data has necessitated the progression of a few of these drugs into clinical trials in order to make the most effective use of interventions in the development of viable targeted therapeutics. The current review presents the understanding of the roles of CXC ligands (CXCLs) and their cognate receptors (CXCRs) in the pathogenesis of several lung diseases such as allergic rhinitis, COPD, lung fibrosis, lung cancer, pneumonia, and tuberculosis. The potential therapeutic benefits of pharmacological or other CXCL/CXCR axis manipulations are also discussed.

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“…Inhibition of the JAK/STAT pathway might have clinical value in severe chronic inflammatory diseases of the airways in general (Georas et al, 2021;Matucci et al, 2021) and severe corticoresistant disease in particular (Barnes 2013, Barnes 2018Subramanian et al, 2021). Furthermore, some literature data suggest that JAK inhibitors can improve the clinical outcome of hospitalized COVID-19 patients (Chen et al, 2021a;Chen et al, 2021b).…”

Section: Jak Inhibitors and Inflammatory Diseases Of The Airwaysmentioning

confidence: 99%

“…Furthermore, the inhibition of JAK1 signaling reduced IFN-γ-stimulated CXCL10 responses and IFN-γenhanced lipopolysaccharide (LPS) responses in alveolar macrophages (Southworth et al, 2012). Accordingly, JAK inhibitors (including ruxolitinib) might constitute a new option for the treatment of inflammatory lung diseases (Wang et al, 2020) like COPD (Southworth et al, 2012;Yew-Booth et al, 2015), severe asthma (O'Connell et al, 2015;Subramanian et al, 2021), severe sarcoidosis (Rotenberg et al, 2018), scleroderma (Lescoat et al, 2020), and rare interferonopathies (Frémond et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Ruxolitinib inhibits cytokine production by human lung macrophages without impairing phagocytic ability

et al. 2022

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Background: The Janus kinase (JAK) 1/2 inhibitor ruxolitinib has been approved in an indication of myelofibrosis and is a candidate for the treatment of a number of inflammatory or autoimmune diseases. We assessed the effects of ruxolitinib on lipopolysaccharide (LPS)- and poly (I:C)-induced cytokine production by human lung macrophages (LMs) and on the LMs’ phagocytic activity.Methods: Human LMs were isolated from patients operated on for lung carcinoma. The LMs were cultured with ruxolitinib (0.5 × 10−7 M to 10–5 M) or budesonide (10–11 to 10–8 M) and then stimulated with LPS (10 ng·ml−1) or poly (I:C) (10 μg·ml−1) for 24 h. Cytokines released by the LMs into the supernatants were measured using ELISAs. The phagocytosis of labelled bioparticles was assessed using flow cytometry.Results: Ruxolitinib inhibited both the LPS- and poly (I:C)-stimulated production of tumor necrosis factor alpha, interleukin (IL)-6, IL-10, chemokines CCL2, and CXCL10 in a concentration-dependent manner. Ruxolitinib also inhibited the poly (I:C)- induced (but not the LPS-induced) production of IL-1ß. Budesonide inhibited cytokine production more strongly than ruxolitinib but failed to mitigate the production of CXCL10. The LMs’ phagocytic activity was not impaired by the highest tested concentration (10–5 M) of ruxolitinib.Conclusion: Clinically relevant concentrations of ruxolitinib inhibited the LPS- and poly (I:C)-stimulated production of cytokines by human LMs but did not impair their phagocytic activity. Overall, ruxolitinib’s anti-inflammatory activities are less intense than (but somewhat different from) those of budesonide—particularly with regard to the production of the corticosteroid-resistant chemokine CXCL-10. Our results indicate that treatment with a JAK inhibitor might be a valuable anti-inflammatory strategy in chronic obstructive pulmonary disease, Th1-high asthma, and both viral and non-viral acute respiratory distress syndromes (including coronavirus disease 2019).

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Ruxolitinib Ameliorates Airway Hyperresponsiveness and Lung Inflammation in a Corticosteroid-Resistant Murine Model of Severe Asthma

Cited by 13 publications

References 89 publications

Autophagy-Related Genes Are Involved in the Progression and Prognosis of Asthma and Regulate the Immune Microenvironment

Autophagy-Related Genes Are Involved in the Progression and Prognosis of Asthma and Regulate the Immune Microenvironment

CXC Chemokines in the Pathogenesis of Pulmonary Disease and Pharmacological Relevance

Ruxolitinib inhibits cytokine production by human lung macrophages without impairing phagocytic ability

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