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

Abstract

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.

Modulation of Human Dendritic Cell Functions by Phosphodiesterase-4 Inhibitors: Potential Relevance for the Treatment of Respiratory Diseases

“…DC activation implies the upregulation of several signature cell surface molecules, marking their transition into the so-called “mature” state. Different from other anti-inflammatory or immuno-modulatory agents, such as corticosteroids, different PDE4 inhibitors, including Tanimilast and Apremilast, neither fully abrogated the acquisition of a mature phenotype nor promoted a classical tolerogenic profile in inflamed DCs [ 6 , 63 , 64 , 65 , 66 ] ( Figure 3 , upper panels). Conversely, PDE4 inhibitors selectively restrained the upregulation of MHC-I and CD80 while sparing the increase of MHC-II, CD83 and CD86.…”

“…Thus, reduction of proinflammatory mediators by PDE4 inhibitors (see Section 4.2.1 .) may block this feedback circuit, resulting in PD-L1 and ILT3/CD85k reduction [ 65 , 68 , 69 ]. The biological significance of this phenomenon remains to be explored.…”

“…Of particular interest, we found that Tanimilast, but not the glucocorticoid budesonide, could strongly induce the expression of CD141 both in moDCs and in circulating cDC2s [ 65 ]. CD141 is a transmembrane protein that is abundantly expressed by endothelial cells, where it is regulated by the levels of intracellular cAMPs [ 70 , 71 ].…”

“…Despite the fact that we could not identify the role of CD141 upregulation in DC activated in the presence of Tanimilast, we found that the percentage of CD141 + correlated with the uptake of dead cells, a function that is crucial to trigger antigen cross-presentation. In addition, we have proposed that CD141 may represent a marker of Tanimilast-induced immunomodulatory DCs [ 65 ].…”

“…Mature DCs secrete a wide range of pro-inflammatory cytokines and chemokines, which, in turn, initiate and amplify inflammation via the recruitment of innate inflammatory cells and the polarization of T lymphocytes [ 79 ]. In this context, the administration of PDE4 inhibitors during DC maturation potently prevented the secretion of prototypic pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and chemokines that are essential for the influx of immune cells into inflamed tissues (CCL3, CXCL9 and 10) [ 6 , 63 , 64 , 65 , 66 ] ( Figure 3 , middle panels). PDE4 inhibitors, including Tanimilast, effectively suppressed Th1/Th17-polarizing cytokines (IL-12, type I IFNs, IL-6 and IL-23) and strongly enhanced the production of CCL22, a Th2/Treg attractor [ 63 , 64 , 65 ].…”