Oral Presentation MIN Spring Retreat 2023

Interleukin-11 produced by myeloid cells drives autoimmune disease pathology (#15)

Ka Yee Fung 1 , Cynthia Louis 1 , Ian Wicks 1 2 , Michael D.W. Griffin 3 , Tracy Putoczki 1
  1. The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Rheumatology Unit, The Royal Melbourne Hospital, , Melbourne, Victoria 3050, Australia
  3. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia

Introduction: Interleukin (IL)-11 is a member of the IL-6 family of cytokines with emerging roles in autoimmune diseases1. The chromosomal region containing the IL-11 gene (19q13) has been linked to Multiple Sclerosis (MS), IL-11 is elevated in the serum of MS patients and in the synovial fluid of arthritis patients. However, our understanding of the biological relevance of this cytokine remains in its infancy.

Methods: We questioned the cellular source of IL-11 in MS and arthritis. To this end, we utilised CRISPR-Cas9 gene editing to generate a novel IL-11 reporter mouse (il11RFP) that allowed for monitoring the cellular source of IL-11 in real-time, without physiological disruption of IL-11 function. We undertook detailed flow cytometry analysis of mice that had undergone experimental autoimmune encephalomyelitis (EAE), a murine model of MS, and antigen-induced arthritis, a pre-clinical model of rheumatoid arthritis. To define the function of each IL-11 expressing cell population that we identified in disease, we generated an il11flox mouse by CRISPR, which was crossed with relevant cell specific Cre-recombinase expressing mice.

Results: Our results reveal that while multiple cell types can produce IL-11, it is the IL-11 produced by myeloid cells that drives disease pathology. We show that myeloid derived IL-11 signals to CD4+T-cells to promote a pathogenic Th17 cytokine signature, demonstrating a new therapeutic opportunity to dampen the inflammation associated with multiple autoimmune pathologies. The therapeutic potential of blocking IL-11 signalling was modelled using il11rKO mice, which mimic systemic administration of a neutralising drug.

Conclusion: We have revealed an unappreciated role for IL-11 in autoimmune pathologies. We define the mechanism by which IL-11 promotes a pathogenic inflammatory response. Together, our results suggest that pharmacological manipulation of IL-11 signalling represents a new therapeutic opportunity.

References:

  1. Fung et al., Emerging roles for IL-11 in inflammatory diseases. Cytokines 2021.155750