Oral Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2024

Monomeric IL-38 is a checkpoint inhibitor of the pattern recognition receptor-interferon axis (#13)

Ina Rudloff 1 2 , Steven X Cho 1 2 , Sarah A Jones 3 , Jan Schroeder 4 , Naiara Bediaga 5 , Joshua Ooi 3 , Matt Johansen 6 , Philip Hansbro 6 , Jose Polo 5 7 , James Whisstock 7 , Eric Morand 3 , Michelle Tate 1 , Andrew Ellisdon 7 , Marcel F Nold 1 8 , Claudia A Nold-Petry 1 8
  1. Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Department of Pediatrics, Monash University, Melbourne, VIC, Australia
  3. Centre for Inflammatory Diseases, Monash University, Melbourne , Australia
  4. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University , Melbourne, VIC, Australia
  5. Adelaide Centre for Epigenetics, School of Biomedicine, University of Adelaide, Adelaide, SA, Australia
  6. Centre for Inflammation, Centenary Institute and University of Technology Sydney, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia
  7. Department of Physiology, Biomedicine Discovery Institute, Monash University, Clayton , VIC, Australia
  8. Department of Paediatrics, Monash University, Melbourne, VIC, Australia

Type I and type III interferons (IFNs) play a key role in host defense on the one hand, but on the other hand they can contribute to the pathogenesis of auto-immune and auto-inflammatory diseases. For example, type I and III IFNs are major drivers of interferonopathies, a group of debilitating diseases predominantly affecting young women and causing substantial long-term, multi-organ morbidity and high mortality. Examples include systemic lupus erythematosus (SLE), dermatomyositis, systemic sclerosis and Sjoegren’s syndrome. Although type I and III IFNs can be induced in multiple ways, activation by pattern recognition receptors (PRRs) is the central pathogenetic pathway in interferonopathies. Therefore, targeted therapies to regulate this PRR-IFN axis are highly sought-after.

Here, we identify interleukin (IL)-38, an IL-1 family member, as the first known endogenous inhibitor of this PRR-IFN axis. In pre-clinical models of SLE such as deficiency of the kinase Lyn, knockout of IL-38 augmented IFN-driven inflammation, including up to 8-fold increases in the IFN-signature genes Irf7, Rsad2 and Oas3 and in the SLE-related pro-inflammatory cytokines IL-6, IL-23, CCL2 and IFNβ itself. IL-38-deficiency also aggravated SLE-like disease activity, including kidney damage. Accordingly, injection of recombinant IL-38 ameliorated inflammation induced by imiquimod, an agonist of the SLE-relevant PRR Toll-like receptor (TLR)7, including reductions in IFNα, IFNβ, IFNγ, IFNλ and IL-6 by up to 98%.

 To decipher signaling mechanisms, we performed experiments in multiple cell lines deficient in pathway intermediates of the PRR-IFN axis. Furthermore, we found that IL-38 can form a domain-swapped homodimer – a property that is novel in the IL-1 cytokine family and rare in cytokine biology overall. Such dimerization attenuated IL-38 activity, while a naturally occurring single nucleotide polymorphism prevented dimerization, thereby increasing IL-38 bioactivity.

 In summary, our study identifies monomeric IL-38 as a promising therapeutic with a novel and differentiated mechanism-of-action, brightening the outlook for millions of patients worldwide suffering from diseases with pathological IFN involvement such as SLE and other interferonopathies.