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.