AUTHOR=Ueki Yoko , Takimoto-Ito Riko , Saito Megumu K. , Tanizaki Hideaki , Kambe Naotomo 

TITLE=Tofacitinib, a suppressor of NOD2 expression, is a potential treatment for Blau syndrome

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1211240

DOI=10.3389/fimmu.2023.1211240

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>Blau syndrome is a rare autosomal dominant autoinflammatory granulomatous disease caused by a mutation in the <italic>NOD2</italic> gene. It is characterized by a clinical trial of granulomatous dermatitis, arthritis, and uveitis. Tofacitinib is a pan Janus kinase (JAK) inhibitor used for treatment of Blau syndrome and idiopathic sarcoidosis. Here, we evaluated its effect on inflammatory pathways associated with Blau syndrome. The effect of tofacitinib on downstream pathways regulated by mutant <italic>NOD2</italic> was analyzed using luciferase assays with overexpression of <italic>NOD2</italic> mutants.</p></sec><sec><title>Methods</title><p>The effect of tofacitinib on the upstream pathway for the induction of <italic>NOD2</italic> expression and proinflammatory cytokine production was assessed using monocytic cell lines differentiated from Blau syndrome patient-derived induced pluripotent stem cells.</p></sec><sec><title>Results</title><p>Tofacitinib did not suppress the increased spontaneous transcriptional activity of NF-κB by mutant <italic>NOD2</italic>. In addition, mutant <italic>NOD2</italic> was not involved in the transcription of ISRE and GAS, which are activated by type 1 and type 2 interferons (IFN), respectively. On the other hand, IFNγ induced the expression of <italic>NOD2</italic>, which led to the production of inflammatory cytokines by an autoinflammatory mechanism only in cells with mutant <italic>NOD2</italic>. </p></sec><sec><title>Discussion</title><p>Tofacitinib suppressed the induction of <italic>NOD2</italic> by IFNγ, thereby inhibiting the production of pro-inflammatory cytokines. Thus, tofacitinib showed anti-inflammatory effects through suppression of <italic>NOD2</italic> expression. The JAK inhibitor tofacitinib is a potential therapeutic agent for Blau syndrome because it suppresses the autoinflammation seen in Blau syndrome by inhibiting the expression of <italic>NOD2</italic>.</p></sec>