Tofacitinib suppresses IL-10/IL-10R signaling and modulates host defense responses in human macrophages.

ABSTRACT JAK inhibitors are increasingly used in dermatology. Despite broad inhibitory effects on cytokine signaling cascades, they only modestly increase the risk for infectious diseases. To address molecular mechanisms underlying this unexpected clinical observation, we investigated how tofacintib, a first-in-class JAK inhibitor, regulates host defense responses in TLR4-activated human macrophages. Specifically, we asked if tofacitinib inhibits anti-inflammatory IL-10 signaling, thereby counteracting downregulation of inflammatory, host-protective pathways. We found that tofacitinib blocked macrophage responses to IL-10 at the level of STAT3 phosphorylation. Furthermore, TLR4-induced, auto-/paracrine IL-10/IL-10R activation promoted expression of hepcidin, the master regulator of iron metabolism, resulting in intracellular iron sequestration. In contrast, auto-/paracrine IL-10/IL-10R activation repressed expression of cathelicidin antimicrobial peptide, as well as antigen-presenting molecules, thus together, inducing a pathogen-favoring environment. While tofacitinib further repressed cathelicidin, it prevented induction of intracellular hepcidin, and restored expression of antigen-presentation molecules in TLR4-activated macrophages. Our study supports the concept that induction of IL-10/IL-10R signaling drives a complex immune evasion strategy of intracellular microbes. Moreover, we conclude that tofacitinib has diverging effects on macrophage host response pathways, and we identify the TLR4-IL-10-STAT3-hepcidin axis as a potential therapeutic target to counteract immune evasion.