JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects

Abstract

The Janus kinase/signal transduction and activator of transcription (JAK-STAT) signaling pathway is implicated in the pathogenesis of inflammatory and autoimmune diseases including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Many cytokines involved in the pathogenesis of autoimmune and inflammatory diseases use JAKs and STATs to transduce intracellular signals. Mutations in JAK and STAT genes cause a number of immunodeficiency syndromes, and polymorphisms in these genes are associated with autoimmune diseases. The success of small-molecule JAK inhibitors (Jakinibs) in the treatment of rheumatologic disease demonstrates that intracellular signaling pathways can be targeted therapeutically to treat autoimmunity. Tofacitinib, the first rheumatologic Jakinib, is US Food and Drug Administration (FDA) approved for rheumatoid arthritis and is currently under investigation for other autoimmune diseases. Many other Jakinibs are in preclinical development or in various phases of clinical trials. This review describes the JAK-STAT pathway, outlines its role in autoimmunity, and explains the rationale/pre-clinical evidence for targeting JAK-STAT signaling. The safety and clinical efficacy of the Jakinibs are reviewed, starting with the FDA-approved Jakinib tofacitinib, and continuing on to next-generation Jakinibs. Recent and ongoing studies are emphasized, with a focus on emerging indications for JAK inhibition and novel mechanisms of JAK-STAT signaling blockade.

Fig. 1

Structure of Janus kinase (JAK) and signal transduction and activation of transcription (STAT) molecules. a Linear structure of JAK molecule showing the different domains. JAKs have four functional domains: the kinase, pseudokinase, Four-point-one protein, Ezrin, Radixin and Moesin domain (FERM), and Src Homology 2 (SH2) domains. The kinase domain is the site of catalytic activity and inhibition by JAK inhibitors (Jakinibs). The FERM and pseudokinase domain interact with the kinase domain and primarily have regulatory functions. An alternative nomenclature for the domains based on their amino acid sequence classifies them as seven Janus homology (JH) domains. b Simplified three-dimensional image of JAK. The crystal structure of the FERM and SH2 domain was recently described and may contribute to receptor recognition. JH1 and JH2 are the kinase and pseudokinase domains respectively. c Linear structure of STAT molecule showing different domains. STAT proteins contain an amino terminal, a coiled coil, a DNA-binding domain (DBD), a linker, an SH2, and a transcriptional activation domain. The TAD domain is located at the C terminus and undergoes serine phosphorylation to recruit additional transcriptional activators. d Simplified three-dimensional image of STAT. Activated STAT dimers form a nutcracker-like structure as shown in this figure. The hinge of the nutcracker is formed by highly conserved SH2 domain and is commonly the target of STAT inhibitors. The linker region and DBD surround centrally located chromatin like the jaws of the nutcracker

Fig. 2

Cytokine signaling through the Janus kinase-signal transduction and activation of transcription (JAK–STAT) pathway. Binding of cytokine to the receptor leads to activation and phosphorylation of JAK and phosphorylation of the receptor. This in turn leads to phosphorylation and dimerization of STAT. Activated STAT dimer migrates to the nucleus and binds to specific DNA-binding sites regulating gene transcription. This culminates in alteration of cellular function

Fig. 3

Physiological significance of Janus kinase (JAK) pathways and mechanism of action of new-generation, small-molecule JAK inhibitors (Jakinibs). Binding of various type I/II cytokines to specific receptor subunits leads to activation of specific JAK pathways. For example, γ-common chain (γc) associates only with JAK3 and mediates signaling of interleukin (IL)-2, IL-4, IL-7, IL-15, and IL-21. However, JAK1 has a broader role in cytokine signaling. Newer generation Jakinibs block specific JAK molecules compared with the first-generation Jakinibs that are non-selective. Thereby, the new-generation Jakinibs should have fewer side effects while maintaining similar efficacy as first-generation Jakinibs. However, some degree of off-target side effects such as cytopenias are seen even with selective Jakinibs such as decernotinib and ABT494. EPO erythropoietin, GH growth hormone, GM-CSF granulocyte macrophage-colony stimulating factor, IFN interferon, TH T-helper, TPO thrombopoietin, TYK tyrosine kinase