Finding Balance in the Immune System the Interplay of IL-38 and IL-36 in Trained Immunity

Researchers Lisa Teufel and Rob Arts from the department of Internal Medicine, led by Leo Joosten and Mihai Netea, work on the anti-inflammatory cytokine interleukin (IL)-38, particularly on its ability to inhibit or dampen trained immunity.

Trained immunity is de facto innate immune memory driven by exposure to pathogens or vaccines as well as to endogenous compounds such as oxidized LDL, urate, fumarate, or IL-1α and IL-1β. The induction of a trained, hyperresponsive phenotype is mediated through epigenetic and metabolic rewiring and, once established, confers non-specific protection against heterologous stimuli. While being beneficial against infectious diseases, a trained phenotype can contribute to conditions characterized by chronic or periodical inflammation such as gout, atherosclerosis, or rarer auto-inflammatory diseases. The endogenous control mechanisms of trained immunity are therefore promising intervention points to develop alternative treatments for inflammatory disorders.

In this context, the group focused on the opposing effects of members of the IL-36 sub-family of cytokines on trained immunity, using different in vitro models to assess the metabolism, epigenetic landscape, and functional properties of primary human monocytes. They showed that recombinant IL-36γ is able to induce trained immunity which was inhibited by the IL-36 receptor antagonist and IL-38.  The inhibitory effect of IL-38 on IL-36γ-induced trained immunity was confirmed in experiments using bone marrow of IL-38 knock out and wild type mice.

These results indicate that exposure to IL-36γ results in long-term pro-inflammatory changes in monocytes which can be inhibited by IL-38. Recombinant IL-38 could therefore potentially be used as a therapeutic intervention for diseases characterised by exacerbated trained immunity. To further investigate this potential, the group is currently including patients with various inflammatory disorders to identify disease targets for IL-38 treatment. Their research has been published in the International Journal of Molecular sciences on 24 January 2023.

Read the study here: Opposing Effects of Interleukin-36γ and Interleukin-38 on Trained Immunity

Teufel, L.U.; Netea, M.G.; van de Veerdonk, F.L.; Dinarello, C.A.; Joosten, L.A.B.; Arts, R.J.W. Opposing Effects of Interleukin-36γ and Interleukin-38 on Trained Immunity. Int. J. Mol. Sci. 2023, 24, 2311. https://doi.org/10.3390/ijms24032311.