Enriched environment enhances NK cell maturation through hypothalamic BDNF in male mice

Abstract

Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous preclinical studies have shown that the enriched environment (EE) confers anti‐obesity and anti‐cancer phenotypes that are associated with enhanced adaptive immunity and are mediated by brain‐derived neurotrophic factor (BDNF). Natural killer (NK) cells have anti‐cancer and anti‐viral properties, and their absence or depletion is associated with inferior clinical outcomes. In this study, we investigated the effects of EE on NK cell maturation following their depletion. Mice living in EE displayed a higher proportion of NK cells in the spleen, bone marrow, and blood, compared to those living in the standard environment (SE). EE enhanced NK cell maturation in the spleen and was associated with upregulation of BDNF expression in the hypothalamus. Hypothalamic BDNF overexpression reproduced the EE effects on NK cell maturation in secondary lymphoid tissues. Conversely, hypothalamic BDNF knockdown blocked the EE modulation on NK cell maturation. Our results demonstrate that a bio‐behavior intervention enhanced NK cell maturation and was mediated at least in part by hypothalamic BDNF.

Identification of Molecular Subtypes and a Prognostic Signature Based on Inflammation-Related Genes in Colon Adenocarcinoma

“…The spleen, bone marrow and blood of mice living in the environment have a higher proportion of Natural killer cells (NK), and EE-stimulated tumour-bearing mice have observed increased maturity of NK cells ( 37 ). Overexpression of BDNF in the hypothalamus replicates the EE-induced NK cell phenotype, while the knock-out of BDNF in the hypothalamus abolishes EE-induced NK regulation ( 38 ). In addition, BDNF is also involved in EE-induced T cell regulation in primary and secondary lymphoid tissues, including the reduction of the total number of splenic T cells and the change (ratio Decrease) of CD4 T helper to CD8 cytotoxic T lymphocytes (CTL) in secondary lymphoid tissue (SLT) ( 39 , 40 ).…”

An enriched environment improves long-term functional outcomes in mice after intracerebral hemorrhage by mechanisms that involve the Nrf2/BDNF/glutaminase pathway

“…A study reported that housing rats in an EE after occlusion of the middle cerebral artery enhances sensorimotor recovery by decreasing BDNF mRNA and protein levels, 68 which is different from the previous report and our current findings. 69 We suggest that the discrepancy may be related to the animal models used and the measurement protocol. Heme oxygenase-1 (HO-1) and the BDNF-mediated pathway are involved in the pathophysiology of depression.…”

Enhancing Effects of Environmental Enrichment on the Functions of Natural Killer Cells in Mice

“…In agreement, splenectomy abrogates the EE-induced tumor-resistant phenotype ( 35 ) implicating splenocytes in tumor resistance. EE also impacts the recovery of NK cells after depletion ( 37 ). We observed a faster NK-cell recovery in the spleen, bone marrow and blood following depletion using anti-asialo-GM1 antibody ( 37 ).…”

“…EE also impacts the recovery of NK cells after depletion ( 37 ). We observed a faster NK-cell recovery in the spleen, bone marrow and blood following depletion using anti-asialo-GM1 antibody ( 37 ).…”

“…Consequently, this treatment reproduced the EE-induced anticancer effects seen in multiple murine cancer models. Furthermore, overexpression of hypothalamic BDNF reproduced EE-induced NK-cell phenotypes characterized with a high percentage of late-stage maturity of NK cells, whereas knockdown of hypothalamic BDNF abrogated EE-induced NK modulation ( 37 ). These data suggest hypothalamic BDNF is a mediator molecule for EE-induced NK cells.…”