IL-36–Induced Toxicity in Neonatal Mice Involves TNF-α Production by Liver Myeloid Cells

Abstract

Human and mouse neonates exhibit limited vaccine responses characterized by predominant Th2 and limited Th1 responses. Because IL-36 exerts a synergic adjuvant effect with IL-12, enhancing Th1 polarization in adult (AD) mice, we administered IL-36β to neonatal (1-wk old) and AD control mice at the time of immunization with tetanus toxoid adsorbed to aluminum hydroxide (TT/Alum). Unexpectedly, the combination of IL-36β with TT/Alum, which was well tolerated in AD mice, proved toxic and even lethal in neonates. This neonatal toxicity was associated with high Il36r mRNA expression in neonatal liver, resulting in increased cytokine production. Liver Il36r mRNA expression decreased with the termination of fetal liver hematopoiesis, and this decrease correlated with a complete protection from TT/Alum/IL-36β–induced mortality. The combination of IL-36β and TT/Alum induced the rapid production of TNF-α and IFN-γ by liver myeloid and lymphoid cells, respectively. These responses were less marked when IL-36β was used alone, with no adverse effect. The toxicity of IL-36β + TT/Alum was abrogated by the administration of a neutralizing anti–TNF-α Ab, confirming causality. In conclusion, liver myeloid cells in neonatal mice are an important source of proinflammatory cytokines that may lead to TNF-α–mediated toxicity and even lethality.

Regulation and function of interleukin‐36 cytokines

“…Accordingly, the production of cytokines in neonate liver was markedly enhanced in response to IL‐36. The toxic effect of the combination of alum and IL‐36 was abrogated by the administration of anti‐TNF‐α antibody consistent with the proinflammatory effect of IL‐36 in neonates …”

Interleukin-36γ is causative for liver damage upon infection with Rift Valley fever virus in type I interferon receptor-deficient mice

“…Interestingly, data revealed a critical role for the novel IL-1 family member IL-36g which was known thus far to play a pro-inflammatory role in some human disorders such as psoriasis, inflammatory bowel disease, pulmonary disease, or rheumatoid arthritis (21)(22)(23)(24). IL-36 cytokines are new members of the IL-1 family which comprise IL-36a, IL-36b, and IL-36g (25)(26)(27). All bind to a heterodimeric receptor composed of the IL-36 receptor (IL-36R) and IL-1 receptor accessory protein (IL-1RAcP).…”

Modulation of interleukin‐36 based inflammatory feedback loop through the hepatocyte‐derived IL‐36R‐P2X7R axis improves steatosis in alcoholic steatohepatitis

“…Hepatocytes act as “epithelial cell‐like” hepatic parenchymal cells; proinflammatory cytokines induce hepatocytes to produce IL‐36γ, and the expression of IL‐36γ is increased in drug‐induced liver injury (Scheiermann et al, 2015). After combined administration of IL‐36β and tetanus toxoid to newborn mice, IL‐36γ mRNA in liver tissue was increased (Palomo et al, 2016), revealing that liver cells also are potential target cells for IL‐36. However, to date, the mechanistic role of the IL‐36/IL‐36R axis in controlling inflammation during alcohol‐related liver diseases is still unclear.…”