A JAK1 Selective Kinase Inhibitor and Tofacitinib Affect Macrophage Activation and Function

Abstract

Background Janus kinases (JAKs) mediate cytokine signaling involved in inflammatory bowel disease. The pan-JAK inhibitor tofacitinib has shown efficacy in the treatment of ulcerative colitis. However, concerns regarding adverse events due to their wide spectrum inhibition fueled efforts to develop selective JAK inhibitors. Given the crucial role of myeloid cells in intestinal immune homeostasis, we evaluated the effect of pan-JAK and selective JAK inhibitors on pro- and anti-inflammatory macrophage polarization and function (M1/M2) and in experimental colitis. Methods Murine bone marrow–derived macrophages or human monocytes were treated using JAK1 and JAK3 selective inhibitors (JAK1i;JAK3i) and tofacitinib and were evaluated by transcriptional, functional, and metabolic analyses. In vivo, oral administration of JAK1i and tofacitinib (10 or 30 mg/kg) was tested in both acute and acute rescue dextran sodium sulfate (DSS) colitis. Results Both tofacitinib and JAK1i but not JAK3i effectively inhibited STAT1 phosphorylation and interferon gamma–induced transcripts in M1 polarized macrophages. Strikingly, transcriptional profiling suggested a switch from M1 to M2 type macrophages, which was supported by increased protein expression of M2-associated markers. In addition, both inhibitors enhanced oxidative phosphorylation rates. In vivo, JAK1i and tofacitinib did not protect mice from acute DSS-induced colitis but ameliorated recovery from weight loss and disease activity during acute rescue DSS-induced colitis at the highest dose. Conclusion JAK1i and tofacitinib but not JAK3i induce phenotypical and functional characteristics of anti-inflammatory macrophages, suggesting JAK1 as the main effector pathway for tofacitinib in these cells. In vivo, JAK1i and tofacitinib modestly affect acute rescue DSS-induced colitis.

Type-I interferons in atherosclerosis

“…In agreement with this observation, in vitro experiments and in vivo animal models revealed that tofacitinib up-regulated ABCA1 expression, promoted anti-inflammatory macrophage polarization, improved EC function, and attenuated atherosclerosis (Table 1 and Fig. 3;De Vries et al, 2019;Furumoto et al, 2017;Pérez-Baos et al, 2017;Wang et al, 2017). However, recently the Oral Surveillance study revealed a statistically significant and clinically relevant increase in pulmonary embolism and an increased mortality in patients older than 50 yr with an increased CV risk when treated with a tofacitinib dose of 10 mg twice daily ( Fig.…”

Intestinal Macrophages in Resolving Inflammation

“…In patients who demonstrate a clinical response to infliximab, a distinct subset of macrophages expressing CD206 is induced and expanded compared with patients who failed to respond to the biologic (79). Furthermore, tofacitinib, a small molecule JAK inhibitor developed for the treatment of IBD as well as other immune-mediated disorders, affects macrophage polarization and function (80,81). Upon treatment with tofacitinib, both murine and human macrophages increase transcription of alternatively activated macrophage markers and increase levels of IL-10 secretion while inhibiting IFN-g signaling, which may help ameliorate weight loss and disease activity and further highlight its therapeutic potential (81).…”

“…Furthermore, tofacitinib, a small molecule JAK inhibitor developed for the treatment of IBD as well as other immune-mediated disorders, affects macrophage polarization and function (80,81). Upon treatment with tofacitinib, both murine and human macrophages increase transcription of alternatively activated macrophage markers and increase levels of IL-10 secretion while inhibiting IFN-g signaling, which may help ameliorate weight loss and disease activity and further highlight its therapeutic potential (81). Hence, there is some indirect evidence that macrophage activation pathways associated with tissue repair and type 2 cytokine responses could be associated with mucosal healing in IBD patients or with the activity of successful therapeutic agents used to treat IBD patients.…”

Tofacitinib in refractory adult-onset Still’s disease: 14 cases from a single centre in China

“…Tofacitibib inhibits the effect of IL-6, IL-10, IFN-γ, INF-α and granulocyte macrophage-colony stimulating factor (GM-CSF), thus suppressing neutrophils NOD-like receptor family pyrin domain-containing 3 (NLRP3) activation and IL-1β production 9. Tofacitinib also suppresses macrophage activation and function 10. It provides some experimental evidence to use tofacitinib in refractory AOSD.…”