Interfering with interferons: targeting the JAK-STAT pathway in complications of systemic juvenile idiopathic arthritis (SJIA)

Abstract

Systemic JIA (SJIA) is distinguished from other forms of JIA by the prevalence of the severe, life-threatening complications macrophage activation syndrome (SJIA-MAS) and lung disease (SJIA-LD). Alternative therapeutics are urgently needed, as disease pathogenesis diverges from what is observed in SJIA, and currently available biologics are insufficient. SJIA-MAS, defined by a cytokine storm and dysregulated proliferation of T-lymphocytes, and SJIA-LD which presents with lymphocytic interstitial inflammation and pulmonary alveolar proteinosis, are both thought to be driven by IFNs, in particular the type II IFN-γ. Involvement of IFNs and a possible crosstalk of type I IFNs with existing biologics indicate a distinct role for the JAK-STAT signalling pathway in the pathogenesis of SJIA-MAS and SJIA-LD. Here, we review this role of JAK-STATs and IFNs in SJIA complications and discuss how new insights of ongoing research are shaping future therapeutic advances in the form of JAK inhibitors and antibodies targeting IFNs.

Keywords: JAK-STAT; interferon; lung disease; macrophage activation syndrome; systemic JIA.

Fig. 1

Interferon-induced JAK-STAT signalling pathways IFN-α/β, IFN-γ and IFNλ signal via distinct receptors, but can share downstream JAK-STAT pathways and signalling molecules. Canonically, IFN-α/β and IFNλ induce assembly of the interferon-stimulated gene factor 3 (ISGF3) which promotes transcription by recognizing and binding to interferon-stimulated response elements (ISREs). IFN-γ canonically leads to the assembly of STAT1 homodimers, which migrate to the nucleus and bind to interferon gamma activation sites (GASs), inducing transcription of ISGs. Unphosphorylated STATs (U-STAT) are also able to facilate transcription via GAS.

Fig. 2

IFN crosstalk and signalling pathway modulation (A) Type I and II IFNs modulate the immune response by epigenomic changes. IFN-γ inhibits the anti-inflammatory response of IL-10 by interfering with STAT3 signalling. IFNα/β signalling via IFNAR and DAMPs/PAMPs signalling via TLRs can work together to induce transcriptional regulation of IL-18. (B) IFNα/β downregulates IL-1α/β by upregulation of IL-10, IL1RA and the decoy IL-1R2 receptor. IL-1 suppresses IFNα/β production via Prostaglandin E2 (PGE2) upregulation. Anakinra/Canakinumab, which blocks IL-1 signalling, can thus promote increased IFNα/β levels.