The PDE4 Inhibitor Tanimilast Blunts Proinflammatory Dendritic Cell Activation by SARS-CoV-2 ssRNAs

Nguyen, Hoang Oanh; Schioppa, Tiziana; Tiberio, Laura; Facchinetti, Fabrizio; Villetti, Gino; Civelli, Maurizio; Prete, Annalisa Del; Sozio, Francesca; Gaudenzi, Carolina; Passari, Mauro; Barbazza, Ilaria; Sozzani, Silvano; Salvi, Valentina; Bosisio, Daniela

doi:10.3389/fimmu.2021.797390

Cited by 11 publications

(17 citation statements)

References 66 publications

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“…Going forward, it has been revealed that Th1-attracting CXCL10 or CXCL9 concentrations were reduced by Tanimilast. Knowing that CXCL10, on which this review focuses on, is one of the most important factors that amplify the immune response through the requirement of Th1 cells, thus, it was suggested that PDE4 inhibitors are a promising therapeutic option for COVID-19 [ 66 ]. Similar to the above-described drugs, Pelargonium sidoides DC .…”

Section: Resultsmentioning

confidence: 99%

What Is Currently Known about the Role of CXCL10 in SARS-CoV-2 Infection?

Gudowska-Sawczuk

Mroczko

2022

IJMS

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Dysregulation of the immune response plays an important role in the progression of SARS-CoV-2 infection. A “cytokine storm”, which is a phenomenon associated with uncontrolled production of large amounts of cytokines, very often affects patients with COVID-19. Elevated activity of chemotactic cytokines, called chemokines, can lead to serious consequences. CXCL10 has an ability to activate its receptor CXCR3, predominantly expressed on macrophages, T lymphocytes, dendritic cells, natural killer cells, and B cells. So, it has been suggested that the chemokine CXCL10, through CXCR3, is associated with inflammatory diseases and may be involved in the development of COVID-19. Therefore, in this review paper, we focus on the role of CXCL10 overactivity in the pathogenesis of COVID-19. We performed an extensive literature search for our investigation using the MEDLINE/PubMed database. Increased concentrations of CXCL10 were observed in COVID-19. Elevated levels of CXCL10 were reported to be associated with a severe course and disease progression. Published studies revealed that CXCL10 may be a very good predictive biomarker of patient outcome in COVID-19, and that markedly elevated CXCL10 levels are connected with ARDS and neurological complications. It has been observed that an effective treatment for SARS-CoV-2 leads to inhibition of “cytokine storm”, as well as reduction of CXCL10 concentrations. It seems that modulation of the CXCL10–CXCR3 axis may be an effective therapeutic target of COVID-19. This review describes the potential role of CXCL10 in the pathogenesis of COVID-19, as well as its potential immune–therapeutic significance. However, future studies should aim to confirm the prognostic, clinical, and therapeutic role of CXCL10 in SARS-CoV-2 infection.

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Section: Resultsmentioning

confidence: 99%

What Is Currently Known about the Role of CXCL10 in SARS-CoV-2 Infection?

Gudowska-Sawczuk

Mroczko

2022

IJMS

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“…Tanimilast displays prominent anti-inflammatory properties in several cell-based models [ 7 , 36 ] as well as in experimental rodent models of pulmonary inflammation [ 17 ] and in clinical settings [ 6 ]. In addition, we have previously demonstrated that it also finely tunes, rather than suppressing, the cytokine network produced by inflamed DCs, thus potentially modulating T cell polarization and adaptive effector functions [ 18 , 37 ]. Here, we characterized TAN-LPS-moDCs as compared to BUD-LPS-moDCs as activators of CD4 + and CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

The PDE4 inhibitor tanimilast shows distinct immunomodulatory properties associated with a type 2 endotype and CD141 upregulation

et al. 2022

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Background Tanimilast is a novel and selective inhaled inhibitor of phosphodiesterase-4 in advanced clinical development for chronic obstructive pulmonary disease (COPD). Tanimilast is known to exert prominent anti-inflammatory activity when tested in preclinical experimental models as well as in human clinical studies. Recently, we have demonstrated that it also finely tunes, rather than suppressing, the cytokine network secreted by activated dendritic cells (DCs). This study was designed to characterize the effects of tanimilast on T-cell polarizing properties of DCs and to investigate additional functional and phenotypical features induced by tanimilast. Methods DCs at day 6 of culture were stimulated with LPS in the presence or absence of tanimilast or the control drug budesonide. After 24 h, DCs were analyzed for the expression of surface markers of maturation and activation by flow cytometry and cocultured with T cells to investigate cell proliferation and activation/polarization. The regulation of type 2-skewing mediators was investigated by real-time PCR in DCs and compared to results obtained in vivo in a randomized placebo-controlled trial on COPD patients treated with tanimilast. Results Our results show that both tanimilast and budesonide reduced the production of the immunostimulatory cytokine IFN-γ by CD4+ T cells. However, the two drugs acted at different levels since budesonide mainly blocked T cell proliferation, while tanimilast skewed T cells towards a Th2 phenotype without affecting cell proliferation. In addition, only DCs matured in the presence of tanimilast displayed increased CD86/CD80 ratio and CD141 expression, which correlated with Th2 T cell induction and dead cell uptake respectively. These cells also upregulated cAMP-dependent immunosuppressive molecules such as IDO1, TSP1, VEGF-A and Amphiregulin. Notably, the translational value of these data was confirmed by the finding that these same genes were upregulated also in sputum cells of COPD patients treated with tanimilast as add-on to inhaled glucocorticoids and bronchodilators. Conclusion Taken together, these findings demonstrate distinct immunomodulatory properties of tanimilast associated with a type 2 endotype and CD141 upregulation in DCs and provide a mechanistic rationale for the administration of tanimilast on top of inhaled corticosteroids.

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“…The GSEA enrichment analysis showed that gene sets grouped according to IGSF6 expression were mainly enriched in cytokine-receptor interaction and intercellular interaction. It has been well established that the antigen peptide-MHCII complex presented by macrophages and DCs is essential for the activation of Th1 cells [28][29][30][31]. Previous studies have also proposed that IGSF6 may be closely related to antigen uptake or the recirculation of DCs [13].…”

Section: Discussionmentioning

confidence: 99%

Immunoglobulin superfamily 6-mediated immune signature determines prognosis and immune landscape in lung adenocarcinoma

Zheng

Wang

Jiang

et al. 2023

Preprint

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Purpose Immunoglobulin superfamily 6 (IGSF6) is a novel member of the immunoglobulin superfamily, and the association of IGSF6 with the prognosis and antitumor immune response in lung adenocarcinoma (LUAD) remains unknown. Here, we aim to identify the role of IGSF6-mediated immune signature in the prognosis and immune landscape of LUAD. Methods IGSF6 expression in pan-cancer and LUAD data from The Cancer Genome Atlas (TCGA) was analyzed by TIMER2.0 and GEPIA2, respectively. Quantitative-real-time-PCR (qRT-PCR), western blot, and immunohistochemistry (IHC) staining were performed to confirm the results of bioinformatics. The association of IGSF6 expression and promoter methylation levels with major clinical features was analyzed by using UALCAN. Survival curves were used to assess the connection between IGSF6 expression and LUAD prognosis. The enrichment analysis was conducted by running the R software clusterProfiler package. TISIDB and TIMER2.0 were utilized to investigate the correlation between IGSF6 and tumor-infiltrating lymphocytes (TILs) in LUAD. Human Protein Atlas (HPA) and flow cytometry (FCM) were used to confirm IGSF6 localization in macrophages. Results IGSF6 levels were decreased in LUAD, and methylation levels at the IGSF6 promoter in LUAD samples increased compared to that in peritumor samples, implying a potential mechanism that leads to the aberrant expression of IGSF6 in LUAD. Low IGSF6 expression was significantly related to poor survival. In addition, IGSF6 expression was closely associated with gene sets involved in immune cell proliferation and exogenous antigen presentation, and it was positively related to immune infiltrates with antitumor activity, including M1 macrophages, dendritic cells (DCs), and T helper 1 (Th1). Furthermore, the IGSF6 protein was mainly located on the membrane of macrophages in LUAD, which enabled exogenous antigen presentation by macrophages to enhance the antitumor immune response. Conclusion IGSF6 is a biomarker of LUAD and IGSF6-mediated immune signature determines the prognosis and immune landscape of LUAD.

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The PDE4 Inhibitor Tanimilast Blunts Proinflammatory Dendritic Cell Activation by SARS-CoV-2 ssRNAs

Cited by 11 publications

References 66 publications

What Is Currently Known about the Role of CXCL10 in SARS-CoV-2 Infection?

What Is Currently Known about the Role of CXCL10 in SARS-CoV-2 Infection?

The PDE4 inhibitor tanimilast shows distinct immunomodulatory properties associated with a type 2 endotype and CD141 upregulation

Immunoglobulin superfamily 6-mediated immune signature determines prognosis and immune landscape in lung adenocarcinoma

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