Why Anti– <scp>IL</scp> ‐17 Therapy Fails: The Role of Autonomous <scp>IL</scp> ‐ <scp>17R</scp> Signaling in Autoimmune Inflammation

The interleukin-17 (IL-17) pathway plays a critical role in orchestrating inflammation in autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), and psoriasis (Pso). Anti–IL-17 monoclonal antibodies are currently used to treat diseases like psoriatic arthritis and spondyloarthritis. However, their limited efficacy in RA and MS highlights the need for a deeper understanding of IL-17 receptor (IL-17R) signaling [1]. Luo et al. unveil a groundbreaking discovery showing that IL-17R signaling can occur independently of its ligand, driven by interactions between Act1 and SHP2 [2]. This novel pathway challenges the established ligand-dependent paradigm and paves the way for innovative therapeutic approaches to refractory autoimmune diseases. IL-17R, a receptor complex consisting of IL-17RA and IL-17RC, typically relies on ligand binding of IL-17A or IL-17F to activate downstream inflammatory pathways. The SEFIR domains of the IL-17R interact with Act1, an adaptor protein critical for signaling cascades. Through Act1, the receptor recruits TRAF proteins, including TRAF6, which activates NF-κB, and TRAF2 and TRAF5, which stabilize proinflammatory mRNAs [3]. Luo et al. identify SHP2 (Src homology 2 domain-containing tyrosine phosphatase) as a key competitor of TRAF5 for Act1 binding. By forming a direct complex with Act1, SHP2 drives IL-17R signaling without requiring IL-17 ligands [3]. Using RNA-sequencing data, the study demonstrates upregulation of the PTPN11 gene (encoding SHP2) in autoimmune conditions, including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). These results were supported by single-cell sequencing data from MS patients and tissue samples from RA and Pso patients. SHP2 expression was even enhanced by IL-17A stimulation. The study further suggests a two-phase model for IL-17R activation. In the first phase, IL-17A binds to its receptor and induces SHP2 upregulation. In the second phase, Act1-SHP2 interactions sustain inflammation, even in the absence of IL-17A (Figure 1). In in vitro conditions, SHP2 overexpression alone led to increased production of proinflammatory cytokines such as CXCL1, CXCL2, and IL-6, comparable to IL-17A treatment. When combined with IL-17A stimulation, SHP2 overexpression further amplified cytokine production. Notably, SHP2 overexpression abrogated the inhibitory effects of anti–IL-17A antibodies. The discovery of this autonomous IL-17R signaling pathway provides a compelling explanation for the limited success of anti–IL-17 therapies in RA and MS. Luo et al. propose iguratimod, a small-molecule anti-inflammatory drug, as a promising alternative. Iguratimod, which is approved for RA in Japan and China, was previously recognized for its inhibition of NF-κB and COX-2 [4]. The authors reveal a novel mechanism where iguratimod disrupts Act1–SHP2 interactions, suppressing both IL-17–dependent and IL-17–independent IL-17R signaling (Figure 1). Iguratimod has shown promising effects in randomized controlled trials in spondyloarthritis, RA, and Sjögren's disease [5]. In China and Japan, iguratimod is approved for the treatment of RA and included as a second-line agent in the Asia-Pacific League of Associations for Rheumatology recommendations for the treatment of RA [6]. The inhibition of SHP2 may also improve systemic lupus erythematosus activity, as shown in a murine model [7]. The novel findings of this study reveal a previously unrecognized alternative mechanism of IL-17R signaling. The results hold immense potential to transform the treatment of chronic inflammatory diseases. The identification of ligand-independent receptor activity raises the question of whether similar mechanisms also occur in other cytokine pathways. F.S.R. writing – original draft, visualization. J.I. writing – original draft. L.C. writing – reviewing and editing. L.C. reports research/non-financial support, advisory fees, and stock ownership from Gilead Sciences, F. Hoffmann-La Roche, Novartis, Pfizer, Bristol-Myers Squibb, Vifor, and Sanofi. All other authors reported no conflict of interest.