Exploring Molecular Mechanisms Involved in the Development of the Depression-Like Phenotype in Interleukin-18-Deficient Mice

Abstract

Interleukin-18 (IL-18) is an inflammatory cytokine that has been linked to energy homeostasis and psychiatric symptoms such as depression and cognitive impairment. We previously revealed that deficiency in IL-18 led to hippocampal abnormalities and resulted in depression-like symptoms. However, the impact of IL-18 deficiency on other brain regions remains to be clarified. In this study, we first sought to confirm that IL-18 expression in neural cells can be found in human brain tissue. Subsequently, we examined the expression of genes in the prefrontal cortex of Il18−/− mice and compared it with gene expression in mice subjected to a chronic mild stress model of depression. Extracted genes were further analyzed using Ingenuity® Pathway Analysis, in which 18 genes common to both the chronic mild stressed model and Il18−/− mice were identified. Of those, 16 were significantly differentially expressed between Il18+/+ and Il18−/− mice. We additionally measured protein expression of α-2-HS-glycoprotein (AHSG) and transthyretin (TTR) in serum and the brain. In the prefrontal cortex of Il18−/− mice, TTR but not AHSG was significantly decreased. Conversely, in the serum of Il18−/− mice, AHSG was significantly increased but not TTR. Therefore, our results suggest that in IL-18-deficit conditions, TTR in the brain is one of the mediators causally related to depression, and AHSG in peripheral organs is one of the regulators inducing energy imbalance. Moreover, this study suggests a possible “signpost” to clarify the molecular mechanisms commonly underlying the immune system, energy metabolism, neural function, and depressive disorders.

Acute stress induces severe neural inflammation and overactivation of glucocorticoid signaling in interleukin-18-deficient mice

“…However, TTR/Ttr was decreased in Il18 −/− mice compared with that in Il18 +/+ mice. According to our previous study, differences in Ttr are commonly detected in the liver, brown adipose tissue, hippocampus, and prefrontal cortex [ 16 – 19 ]. Although mRNA expression of Ttr was not significantly altered, its protein expression in the hippocampus was significantly decreased in both stressed Il18 +/+ and Il18 −/− mice compared with that in non-stressed mice.…”

“…Total RNA purification was performed as previously described [ 19 ]. Briefly, we extracted total RNA using an ISOGEN kit (cat.…”

“…Core analysis was performed to analyze the functions of extracted molecules as follows: tissue, hippocampus; all other settings, default. The network explorer of IPA was used with default settings to identify molecule-molecule interactions and pathways between molecules [ 19 ].…”

“…In our previous studies, we found that IL18 was associated with energy metabolism and psychiatric disorders such as depression [ 16 – 18 ]. Regarding neural function, IL18 exists in neural cells of the brain in a precursor form, and its deficiency leads to hippocampal impairment and a depressive-like phenotype [ 18 , 19 ]. Thus, IL18 is closely related to neural function and psychiatric phenotypes such as depression as well as the immune system.…”

Molecular Mechanisms of IL18 in Disease

“…Interleukin (IL) 18 was initially cloned in 1995 and identified as a proinflammatory cytokine that stimulates type 1 helper T cells to produce interferon (IFN)-γ [1]. The 23-kDa precursor form of IL18 is activated by cleaved caspase-1 and secreted as an active, 18-kDa mature form [2][3][4][5][6]. IL18 is secreted by hematopoietic lineages, such as macrophage cells [1] and microglia [7], as well as non-immune cells such as neural cells [6].…”