ID: 129: Role of the IL-36 pathway in inflammatory responses in mouse neonates
Background: IL-36 synergizes with IL-12 to induce T helper (Th)1 differentiation. To investigate IL-36’s TH1-biased immunostimulatory potential, neonates (1wk-old) were immunized with aluminum (Alum)-adsorbed tetanus toxoid (TT/Alum) and recombinant IL-36 β . Unexpectedly, the combination of IL-36 β (0.1  μ g/g) with TT/Alum resulted in rapid mortality, which was not observed in 1 wk old IL-36R deficient or in adult wild-type mice. Objective: Understand the mechanisms of IL-36-induced toxicity in early life. Methods: 1 wk-, 3 wk- old (infants) and adult (6–8 wk) mice were immunized with TT/Alum, different doses of IL-36 β or a combination thereof. Cytokine levels were measured in serum and organ total RNA. Liver and spleen lymphoid and myeloid cells were sorted. Results: Upon IL-36 injection, mRNA levels of TNF- α , IFN- γ , and of several other cytokines were significantly and specifically increased in the liver of neonates, as compared to 3 wkold and adult mice. Liver IL-36R mRNA levels were elevated in neonates and rapidly decreased with age, which correlated with a higher number of leukocytes, especially B cells, monocytes and neutrophils in neonatal liver. IL-36R mRNA was expressed in dendritic cells,and to a lesser extent in B cells, T cells, NK/NKT cells, monocytes and neutrophils. TNF- α and IFN- γ were mainly produced by myeloid (monocytes and neutrophils) and lymphoid (NK1.1+ and T cells) cells respectively. Importantly, mice injected with a monoclonal anti-TNF- α antibody were fully protected from IL-36-induced lethality. Conclusion: IL-36-induced toxicity in neonates is associated with a higher number of liver IL-36R expressing myeloid cells, leading to excessive TNF- α production.