Abstract
Phosphodiesterase 4 (PDE4) inhibitors are immunomodulatory drugs approved to treat diseases associated with chronic inflammatory conditions, such as COPD, psoriasis and atopic dermatitis. Tanimilast (international non-proprietary name of CHF6001) is a novel, potent and selective inhaled PDE4 inhibitor in advanced clinical development for the treatment of COPD. To begin testing its potential in limiting hyperinflammation and immune dysregulation associated to SARS-CoV-2 infection, we took advantage of an in vitro model of dendritic cell (DC) activation by SARS-CoV-2 genomic ssRNA (SCV2-RNA). In this context, Tanimilast decreased the release of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (CCL3, CXCL9, and CXCL10) and of Th1-polarizing cytokines (IL-12, type I IFNs). In contrast to β-methasone, a reference steroid anti-inflammatory drug, Tanimilast did not impair the acquisition of the maturation markers CD83, CD86 and MHC-II, nor that of the lymph node homing receptor CCR7. Consistent with this, Tanimilast did not reduce the capability of SCV2-RNA-stimulated DCs to activate CD4+ T cells but skewed their polarization towards a Th2 phenotype. Both Tanimilast and β-methasone blocked the increase of MHC-I molecules in SCV2-RNA-activated DCs and restrained the proliferation and activation of cytotoxic CD8+ T cells. Our results indicate that Tanimilast can modulate the SCV2-RNA-induced pro-inflammatory and Th1-polarizing potential of DCs, crucial regulators of both the inflammatory and immune response. Given also the remarkable safety demonstrated by Tanimilast, up to now, in clinical studies, we propose this inhaled PDE4 inhibitor as a promising immunomodulatory drug in the scenario of COVID-19.
Highlights
SARS coronavirus 2 (SARS-CoV-2), the causative agent of the pandemic Coronavirus disease 2019 (COVID-19), is a positivesense ssRNA virus belonging to the family of Coronaviridae [1]
Tanimilast Selectively Reduces the Secretion of Cytokines and Chemokines by moDCs Stimulated With SCV2-RNA (SCV2-moDCs)
The effects of Tanimilast on the pro-inflammatory properties of SCV2-moDCs were assessed in terms of cytokine and chemokine regulation. moDCs were pre-treated with Tanimilast (10-11, 10-9, 10-7 M) for 1 hour and stimulated with an optimal concentration of SCV2-RNA [4]
Summary
SARS coronavirus 2 (SARS-CoV-2), the causative agent of the pandemic Coronavirus disease 2019 (COVID-19), is a positivesense ssRNA virus belonging to the family of Coronaviridae [1]. SCV2-RNA recapitulated potent lung inflammation in vivo and induced a strong release of proinflammatory cytokines and Th1 polarization in vitro. Inhibition of PDE4 leads to accumulation of intracellular cAMP and to a shift of the anti-inflammatory/pro-inflammatory balance [8] Such upstream anti-inflammatory mechanism, makes these agents interesting to master critical conditions characterized by overt release of multiple cytokines, as compared to other single downstream anti-cytokine drugs [9]. Side effects such as gastrointestinal disturbances, nausea and emesis as well as headache and weight loss are typically associated with oral PDE4 inhibitors [10]. Published data by our group highlighted that Tanimilast can reduce the secretion of inflammatory and Th1/Th17 polarizing cytokines by fine tuning the activity of the master inflammatory transcription factor NF-kB, which could be useful to control Th-1 and Th-17 driven pathologies without inducing a global repression of the inflammatory and immune responses [15]
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