Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus: Integration of Distinct Inflammatory Pathways and the Prospect of Their Inhibition with an Oral Agent

Abstract

Four Janus kinases (JAKs) (JAK1, JAK2, JAK3, TYK2) and seven signal transducers and activators of transcription (STATs) (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) mediate the signal transduction of more than 50 cytokines and growth factors in many different cell types. Located intracellularly and downstream of cytokine receptors, JAKs integrate and balance the actions of various signaling pathways. With distinct panels of STAT-sensitive genes in different tissues, this highly heterogeneous system has broad in vivo functions playing a crucial role in the immune system. Thus, the JAK/STAT pathway is critical for resisting infection, maintaining immune tolerance, and enforcing barrier functions and immune surveillance against cancer. Breakdowns of this system and/or increased signal transduction may lead to autoimmunity and other diseases. Accordingly, the recent development and approval of the first small synthetic molecules targeting JAK molecules have opened new therapeutic avenues of potentially broad therapeutic relevance. Extensive data are now available regarding the JAK/STAT pathway in rheumatoid arthritis. Dysregulation of the cytokines is also a hallmark of systemic lupus erythematosus (SLE), and targeting the JAK/STAT proteins allows simultaneous suppression of multiple cytokines. Evidence from in vitro studies and animal models supports a pivotal role also in the pathogenesis of cutaneous lupus and SLE. This has important therapeutic implications, given the current paucity of targeted therapies especially in the latter. Herein, we summarize the currently available literature in experimental SLE, which has led to the recent promising Phase II clinical trial of a JAK inhibitor.

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“…2), while IL-1, IL-6, and TNF receptor activation feeds into pro-inflammatory cytokine expression though the transcription factor NFκB ( Fig. 2) [85][86][87]. Activation and priming of innate and adaptive immune responses should result in pathogen clearance and recovery.…”

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“…This is not surprising as JAK mutations have been identified in immune deficiency syndromes including severe combined immune deficiency (SCID), in hematologic malignancies (leukemias and lymphomas) [ 28 ], and also in autoimmunity (hyper IgE-Job’s syndrome) [ 29 ]. Some of the mutations in the JAK/STAT pathway directly increase the risk of developing well characterized autoimmune disorders like inflammatory bowel disease, psoriasis, ankylosing spondylitis, Behçet’s disease [ 30 , 31 , 32 ], RA, Sjögren syndrome, or systemic lupus erythematosus (SLE) [ 33 , 34 ]. These findings underline the role of cytokine mediated regulation that affects such important pathophysiological processes as IFN-mediated immunity [ 35 , 36 ], T- and NK-cell-based immune response, regulation of function of lymphocytes, hematopoiesis, and nerve development.…”

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“…These pro-inflammatory cytokines were noted to be released into the blood of affected patients [27,28]. [29][30][31][32]. Additionally, the binding of DAMPs with RLRs triggers the synthesis of inflammasomes, which trigger the conversion/maturation of procaspase-1 to caspase-1 and pro IL-1β to IL-1β, which are potent pro-inflammatory cytokines [33].…”