Early life stress from allergic dermatitis causes depressive-like behaviors in adolescent male mice through neuroinflammatory priming.

Allergic dermatitis (AD), associated with pruritus and itchiness, is one of the major stressful conditions early in life. AD also influences the incidence of neuropsychiatric disorders and developmental disorders through neuro-immune interactions. To the best of our knowledge, there is no report that assesses the effects of early childhood dermatitis on psychiatric disorders later in life using an animal model. Here, we developed an oxazolone (Ox)-induced AD model in the early life of male C57BL/6J mice whose ears were challenged by Ox repeatedly from postnatal days (PD) 2 to PD30. On PD30, the Ox-treated ears were remarkably thickened and showed epidermal hyperplasia coupled with increased expression of T helper 2 cytokines, interleukin (IL)-4, and IL-13 in the ear tissue. Additionally, serum immunoglobulin E levels and serum corticosterone levels were higher in the Ox-treated mice than those in the control mice. Although Ox-treated PD40 mice showed neither behavioral abnormalities nor increases in pro-inflammatory cytokine expression in the brain, this study revealed that they experienced downregulation of CD200R1 expression in the amygdala under basal conditions and that additional lipopolysaccharide (LPS) administration induced enhanced neuroinflammatory reaction as the priming effect was accompanied by an increase of Iba-1-positive microglia in the amygdala and hippocampus. Furthermore, the Ox-treated PD40 mice showed depressive-like behaviors 24 h after LPS administration, whereas the control mice did not. Interestingly, the expression of indoleamine 2,3-dioxygenase and kynurenine 3-monooxygenase, key rate-limiting enzymes of the kynurenine metabolism pathway, was upregulated in the hippocampus, prefrontal cortex, and amygdala of the Ox-treated mice 4 h after LPS administration. Based on these results, we suggest that early life stress from AD aggravates susceptibility to systemic inflammation in the adolescent brain, leading to depressive behaviors with abnormal kynurenine metabolism.

Collaboration of cancer-associated fibroblasts and tumour-associated macrophages for neuroblastoma development.

Neuroblastoma is the most common extracranial solid tumour in children and is histologically classified by its Schwannian stromal cells. Although having fewer Schwannian stromal cells is generally associated with more aggressive phenotypes, the exact roles of other stromal cells (mainly macrophages and fibroblasts) are unclear. Here, we examined 41 cases of neuroblastoma using immunohistochemistry for the tumour-associated macrophage (TAM) markers CD68, CD163, and CD204, and a cancer-associated fibroblast (CAF) marker, alpha smooth muscle actin (αSMA). Each case was assigned to low/high groups on the basis of the number of TAMs or three groups on the basis of the αSMA-staining area for CAFs. Both the number of TAMs and the area of CAFs were significantly correlated with clinical stage, MYCN amplification, bone marrow metastasis, histological classification, histological type, and risk classification. Furthermore, TAM settled in the vicinity of the CAF area, suggesting their close interaction within the tumour microenvironment. We next determined the effects of conditioned medium of a neuroblastoma cell line (NBCM) on bone marrow-derived mesenchymal stem cells (BM-MSCs) and peripheral blood mononuclear cell (PBMC)-derived macrophages in vitro. The TAM markers CD163 and CD204 were significantly up-regulated in PBMC-derived macrophages treated with NBCM. The expression of αSMA by BM-MSCs was increased in NBCM-treated cells. Co-culturing with CAF-like BM-MSCs did not enhance the invasive ability but supported the proliferation of tumour cells, whereas tumour cells co-cultured with TAM-like macrophages had the opposite effect. Intriguingly, TAM-like macrophages enhanced not only the invasive abilities of tumour cells and BM-MSCs but also the proliferation of BM-MSCs. CXCL2 secreted from TAM-like macrophages plays an important role in tumour invasiveness. Taken together, these results indicate that PBMC-derived macrophages and BM-MSCs are recruited to a tumour site and activated into TAMs and CAFs, respectively, followed by the formation of favourable environments for neuroblastoma progression. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Hypoxia induces tumor aggressiveness and the expansion of CD133-positive cells in a hypoxia-inducible factor-1α-dependent manner in pancreatic cancer cells.

BACKGROUND: Intratumoral hypoxia is known to lead to increased aggressiveness and distant metastasis. However, the interplay underlying these actions is still unknown. OBJECTIVE: We explored whether cancer cells might acquire a stem-like phenotype under hypoxia, consequently leading to an aggressive phenotype, including invasiveness and metastasis. METHODS: Under normoxia (20% O(2)) or hypoxia (1% O(2)), the expression of CD133 (cancer stem cell marker), CXC chemokine receptor 4 (CXCR4) and hypoxia-inducible factor-1α (HIF-1α) was examined by RT-PCR and immunostaining using human pancreatic cancer cell lines. We also examined if hypoxia facilitates the invasiveness of CD133+ cancer cells. Furthermore, we transfected dominant active HIF-1α (HIF-1αΔODD) by the retroviral gene transfer and examined the effects both in vitro and in vivo. RESULTS: Compared with normoxia, hypoxia elevated the expression of CD133, CXCR4 and HIF-1α. Moreover, hypoxia facilitated the invasiveness of CD133+ pancreatic cancer cells. The behavior of HIF-1αΔODD-transfected cells under normoxia was compatible with that of the parent cells under hypoxia. Furthermore, a xenograft model of HIF-1αΔODD cells showed aggressiveness, including metastasis and highly tumorigenic ability. CONCLUSION: Hypoxia induces tumor aggressiveness associated with the expansion of CD133+ pancreatic cancer cells in a predominantly HIF-1α-dependent manner.

Combined interleukin-6 and interleukin-1 deficiency causes obesity in young mice.

Proinflammatory cytokines including interleukin (IL)-1 and IL-6 exert pleiotropic effects on the neuro-immuno-endocrine system. Previously, we showed that IL-1 receptor antagonist-deficient (IL-1Ra(-/-)) mice show a lean phenotype due to an abnormal lipid metabolism. On the contrary, it was reported that IL-6(-/-) mice exhibit obesity after 6 months of age. This study sought to assess the roles of IL-1 and IL-6 in body weight homeostasis. We generated mice deficient in IL-6 and IL-1Ra (IL-6(-/-) IL-1Ra(-/-)) and IL-6, IL-1alpha, and IL-1beta (IL-6(-/-) IL-1(-/-)). IL-6(-/-) IL-1Ra(-/-) mice exhibited a lean phenotype, similar to IL-1Ra(-/-) mice. On the other hand, IL-6(-/-) IL-1(-/-) mice became obese as early as 10 weeks of age, while IL-1(-/-) mice and IL-6(-/-) mice were normal at this age. The daily food intake was significantly higher in IL-6(-/-) IL-1(-/-) mice than in IL-6(-/-) IL-1(+/-) mice, while energy expenditure was comparable in these two strains. Acute anorexia induced by peripheral administration of IL-1 was significantly suppressed in IL-6(-/-) IL-1(-/-) mice, but not in IL-1(-/-) mice or IL-6(-/-) mice compared with wild-type mice. These results indicate that IL-1 and IL-6 are both involved in the regulation of body fat in a redundant manner in young mice.