The activation of spinal cord glial cells has been implicated in the development of neuropathic pain upon peripheral nerve injury. The molecular mechanisms underlying glial cell activation, however, have not been clearly elucidated. In this study, we found that damaged sensory neurons induce the expression of tumor necrosis factor-α, interleukin-1β, interleukin-6, and inducible nitric-oxide synthase genes in spinal cord glial cells, which is implicated in the development of neuropathic pain. Studies using primary glial cells isolated from toll-like receptor 2 knock-out mice indicate that damaged sensory neurons activate glial cells via toll-like receptor 2. In addition, behavioral studies using toll-like receptor 2 knock-out mice demonstrate that the expression of toll-like receptor 2 is required for the induction of mechanical allodynia and thermal hyperalgesia due to spinal nerve axotomy. The nerve injury-induced spinal cord microglia and astrocyte activation is reduced in the toll-like receptor 2 knock-out mice. Similarly, the nerve injury-induced pro-inflammatory gene expression in the spinal cord is also reduced in the toll-like receptor 2 knock-out mice. These data demonstrate that toll-like receptor 2 contributes to the nerve injury-induced spinal cord glial cell activation and subsequent pain hypersensitivity.

This review provides an overview of the importance of microbiota in the regulation of gut–brain communication in immune-related neurological disorders. The gastrointestinal (GI) tract hosts a diverse abundance of microbiota, referred to as gut microbiota. The gut microbiota plays a role in the maintenance of GI tract homeostasis and is likely to have multiple effects on brain development and function. The bidirectional communication between the gut microbiota and the brain is termed the microbiota–gut–brain axis. This communication between the intestine and the brain appears to affect human health and behavior, as certain animal studies have demonstrated the association between alterations in the gut microbiota and neurological disorders. Most insights about the microbiota–gut–brain axis come from germ-free animal models, which reveal the importance of gut microbiota in neural function. To date, many studies have observed the impact of the gut microbiota in patients with neurological disorders. Although many studies have investigated the microbiota–gut–brain axis, there are still limitations in translating this research to humans given the complexities of the relationship between the gut microbiota and the brain. In this review, we discuss emerging evidence of how the microbiota–gut–brain axis regulates brain development and function through biological networks, as well as the possible contribution of the microbiota–gut–brain axis in immune-related neurological disorders.

Microglial cells are activated during excitotoxin-induced neurodegeneration. However, the in vivo role of microglia activation in neurodegeneration has not yet been fully elucidated. To this end, we used Ikkβ conditional knockout mice (LysM-Cre/Ikkβ^F/F) in which the Ikkβ gene is specifically deleted in cells of myeloid lineage, including microglia, in the CNS. This deletion reduced IκB kinase (IKK) activity in cultured primary microglia by up to 40% compared with wild-type (Ikkβ^F/F), and lipopolysaccharide-induced proinflammatory gene expression was also compromised. Kainic acid (KA)-induced hippocampal neuronal cell death was reduced by 30% in LysM-Cre/Ikkβ^F/F mice compared with wild-type mice. Reduced neuronal cell death was accompanied by decreased KA-induced glial cell activation and subsequent expression of proinflammatory genes such as tumour necrosis factor (TNF)-α and interleukin (IL)-1β. Similarly, neurons in organotypic hippocampal slice cultures (OHSCs) from LysM-Cre/Ikkβ^F/F mouse brain were less susceptible to KA-induced excitotoxicity compared with wild-type OHSCs, due in part to decreased TNF-α and IL-1β expression. Based on these data, we concluded that IKK/nuclear factor-κB dependent microglia activation contributes to KA-induced hippocampal neuronal cell death in vivo through induction of inflammatory mediators.

Metformin, a Type II diabetic treatment drug, which inhibits transcription of gluconeogenesis genes, has recently been shown to lower the risk of some diabetes-related tumors, including breast cancer. Recently, “cancer stem cells” have been demonstrated to sustain the growth of tumors and are resistant to therapy. To test the hypothesis that metformin might be reducing the risk to breast cancers, the human breast carcinoma cell line, MCF-7, grown in 3-dimensional mammospheres which represent human breast cancer stem cell population, were treated with various known and suspected breast cancer chemicals with and without non-cytotoxic concentrations of metformin. Using OCT4 expression as a marker for the cancer stem cells, the number and size were measured in these cells. Results demonstrated that TCDD (100 nM) and bisphenol A (10 µM) increased the number and size of the mammospheres, as did estrogen (10 nM E2). By monitoring a cancer stem cell marker, OCT4, the stimulation by these chemicals was correlated with the increased expression of OCT4. On the other hand, metformin at 1 and 10 mM concentration dramatically reduced the size and number of mammospheres. Results also demonstrated the metformin reduced the expression of OCT4 in E2 & TCDD mammospheres but not in the bisphenol A mammospheres, suggesting different mechanisms of action of the bisphenol A on human breast carcinoma cells. In addition, these results support the use of 3-dimensional human breast cancer stem cells as a means to screen for potential human breast tumor promoters and breast chemopreventive and chemotherapeutic agents.

Toll-like receptors (TLRs) are type I transmembrane signaling molecules that are expressed in cells of the innate immune system. In these cells, TLRs function as pattern recognition receptors (PRR) that recognize specific molecular patterns derived from microorganisms. Upon activation, TLRs trigger a cascade of intracellular signaling pathways in innate immune cells, leading to the induction of inflammatory and innate immune responses, which in turn regulate adaptive immune responses. In the nervous system, different members of the TLR family are expressed on glial cells (astrocytes, microglia, oligodendrocytes, and Schwann cells) and neurons. Recently, increasing evidence has supported the idea that TLRs also recognize endogenous molecules that are released from damaged tissue, thereby regulating inflammatory responses and subsequent tissue repair. These findings imply that TLRs on glial cells may also be involved in the inflammatory response to tissue damage in the nervous system. In this review, we discuss recent studies on TLR expression in the cells of the nervous system and their roles in acute neurological disorders involving tissue damage such as strokes, traumatic spinal cord and brain injuries, and peripheral nerve injuries.