Jialin Zheng

Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders

Brain inflammation is a complex cellular and molecular response to stress, injury or infection of the CNS in attempt to defend against insults, clear dead and damaged neurons and return the CNS to a normal state. Inflammation in the CNS is driven by the activation of resident microglia, astrocytes and infiltrating peripheral macrophages, which release a plethora of anti‐ and pro‐inflammatory cytokines, chemokines, neurotransmitters and reactive oxygen species. This inflammatory state inadvertently causes further bystander damage to neurons and produces both detrimental and favorable conditions for neurogenesis. Inflammatory factors have varying effects on neural progenitor cell proliferation, migration, differentiation, survival and incorporation of newly born neurons into the CNS circuitry. The unique profile of inflammatory factors, which depends on the severity of inflammation, can have varying consequences on neurogenesis. Inflammatory factors released during mild acute inflammation usually stimulate neurogenesis; where as the factors released by uncontrolled inflammation create an environment that is detrimental to neurogenesis. This review will provide a summary of current progress in this emerging field and examine the potential mechanisms through which inflammation affects neurogenesis during neurological complications.

Suppression of Inflammatory Neurotoxins by Highly Active Antiretroviral Therapy in Human Immunodeficiency Virus—Associated Dementia

A human immunodeficiency virus type 1 (HIV)-seropositive, antiretroviral-naive patient presented with significant cognitive dysfunction. Neuropsychologic, neuroradiologic, immunologic, and virologic studies confirmed HIV-associated dementia (HAD). After 12 weeks of highly active antiretroviral therapy (HAART) with ibuprofen, dramatic improvements were demonstrated in neurologic function and were sustained for > 1 year. HIV-1 RNA in cerebrospinal fluid (CSF) decreased from 10(5) to 10(4) copies/mL after 4 weeks. After 20 weeks of therapy, plasma viremia decreased from 10(6) copies/mL to undetectable (< 96 copies/mL). Assays of neurotoxins (tumor necrosis factor-alpha, quinolinic acid, and nitric oxide) in plasma and CSF were considerably elevated at presentation and significantly decreased after therapy. Baseline plasma and CSF demonstrated neurotoxic activities in vitro, which also reduced markedly. These data, taken together, support the notion that HAD is a reversible metabolic encephalopathy fueled by viral replication. HAART used with nonsteroidal antiinflammatory agents leads to the suppression of inflammatory neurotoxins and can markedly improve neurologic function in HAD.

Mononuclear phagocytes mediate blood-brain barrier compromise and neuronal injury during HIV-1-associated dementia

The neuropathogenesis of HIV‐1 infection revolves around the production of secretory factors from immune‐activated brain mononuclear phagocytes (MP). MP‐secreted chemokines may play several roles in HIV‐1 encephalitis (HIVE). These can promote macrophage brain infiltration, blood‐brain barrier (BBB) and neuronal dysfunction during HIV‐1‐associated dementia. We investigate how HIV‐1‐infected MP regulates the production of chemokines and how they influence HIV‐1 neuropathogenesis. We demonstrate that HIV‐1‐infected and immune‐activated MP (for example, microglia) and astrocytes produce β‐chemokines in abundance, as shown in both laboratory assays and within infected brain tissue. HIV‐1‐infected microglia significantly modulate monocyte migration in a BBB model system and in brains of SCID mice with HIVE. HIV‐1‐infected MP down‐regulate tight junction protein and special polarized transport systems on brain microvascular endothelial cells as shown in human autopsy brain tissue and in SCID mice with HIVE. Chemokines can damage neurons directly. Toxicity caused by binding of stromal‐derived factor‐1α to its receptor on neurons exemplifies such mechanism. In toto, these works underscore the diverse roles of chemokines in HIV‐1 neuropathogenesis and lay the foundation for future therapeutic interventions.

Stromal cell-derived factor 1-mediated CXCR4 signaling in rat and human cortical neural progenitor cells.

Stromal cell‐derived factor 1 (SDF‐1) and the chemokine receptor CXCR4 are highly expressed in the nervous system. Knockout studies have suggested that both SDF‐1 and CXCR4 play essential roles in cerebellar, hippocampal, and neocortical neural cell migration during embryogenesis. To extend these observations, CXCR4 signaling events in rat and human neural progenitor cells (NPCs) were examined. Our results show that CXCR4 is expressed in abundance on rat and human NPCs. Moreover, SDF‐1α induced increased NPCs levels of inositol 1,4,5‐triphosphate, extracellular signal‐regulated kinases 1/2, Akt, c‐Jun N‐terminal kinase, and intracellular calcium whereas it diminished cyclic adenosine monophosphate. Finally, SDF‐1α can induce human NPC chemotaxis in vitro, suggesting that CXCR4 plays a functional role in NPC migration. Both T140, a CXCR4 antagonist, and pertussis toxin (PTX), an inactivator of G protein‐coupled receptors, abrogated these events. Ultimately, this study suggested that SDF‐1α can influence NPC function through CXCR4 and that CXCR4 is functional on NPC.

IL-1β and TNF-α induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase.

Glutaminase 1 is the main enzyme responsible for glutamate production in mammalian cells. The roles of macrophage and microglia glutaminases in brain injury, infection, and inflammation are well documented. However, little is known about the regulation of neuronal glutaminase, despite neurons being a predominant cell type of glutaminase expression. Using primary rat and human neuronal cultures, we confirmed that interleukin‐1β (IL‐1β) and tumor necrosis factor‐α (TNF‐α), two pro‐inflammatory cytokines that are typically elevated in neurodegenerative disease states, induced neuronal death and apoptosis in vitro. Furthermore, both intracellular and extracellular glutamate levels were significantly elevated following IL‐1β and/or TNF‐α treatment. Pre‐treatment with N‐Methyl‐d‐aspartate (NMDA) receptor antagonist MK‐801 blocked cytokine‐induced glutamate production and alleviated the neurotoxicity, indicating that IL‐1β and/or TNF‐α induce neurotoxicity through glutamate. To determine the potential source of excess glutamate production in the culture during inflammation, we investigated the neuronal glutaminase and found that treatment with IL‐1β or TNF‐α significantly upregulated the kidney‐type glutaminase (KGA), a glutaminase 1 isoform, in primary human neurons. The up‐regulation of neuronal glutaminase was also demonstrated in situ in a murine model of HIV‐1 encephalitis. In addition, IL‐1β or TNF‐α treatment increased the levels of KGA in cytosol and TNF‐α specifically increased KGA levels in the extracellular fluid, away from its main residence in mitochondria. Together, these findings support neuronal glutaminase as a potential component of neurotoxicity during inflammation and that modulation of glutaminase may provide therapeutic avenues for neurodegenerative diseases.

CXCL12 Increases Human Neural Progenitor Cell Proliferation Through Akt-1/FOXO3a Signaling Pathway

CXCL12, a ligand for the chemokine receptor CXCR4, is well known in mediating neural progenitor cell (NPC) migration during neural development. However, the effects of CXCL12 on human NPC proliferation and its associated signaling pathways remain unclear. The transcription factor, FOXO3a, a downstream target of Akt‐1, is critical for cell cycle control and may also play an important role in regulating NPC proliferation. In this study, we found that CXCL12 promotes human NPC proliferation as determined by the proliferation marker Ki67 and BrdU incorporation. This CXCL12‐mediated NPC proliferation was associated with an increase in Akt‐1 and FOXO3a phosphorylation in a time‐ and dose‐dependent manner. The CXCR4 antagonist (T140) or inhibitors for G proteins (Pertussis toxin) and phosphoinositide 3‐kinase (PI3K) (LY294002) abolished CXCL12‐mediated NPC proliferation and phosphorylation of Akt‐1 and FOXO3a. The roles of Akt‐1 and FOXO3a in CXCL12‐mediated NPC proliferation were further investigated by using adenoviral over‐expression in NPCs. Over‐expression of dominant‐negative Akt‐1 or wild‐type FOXO3a in NPC abrogated CXCL12‐mediated proliferation. These data suggest that CXCL12‐mediated NPC proliferation is reliant upon the phosphorylation of Akt‐1 and FOXO3a and gives insight to an essential role of CXCL12 in neurogenesis. Understanding this mechanism may facilitate the development of novel therapeutic targets for NPC proliferation during neurogenesis.

Plasma Levels of Soluble CD14 and Tumor Necrosis Factor-α Type II Receptor Correlate with Cognitive Dysfunction during Human Immunodeficiency Virus Type 1 Infection

The relationship between monocyte immune responses and cognitive impairment during progressive human immunodeficiency virus type 1 (HIV-1) infection was investigated in 28 subjects receiving highly active antiretroviral therapy. The mean+/-SEM CD4(+) T lymphocyte count and virus load for all patients were 237+/-41 cells/mm(3) and 77,091+/-195,372 HIV-1 RNA copies/mL, respectively. Levels of soluble tumor necrosis factor-alpha type II receptor (sTNF-RII) and soluble CD14 (sCD14) were measured in plasma by ELISA and were correlated with results from neuropsychological, magnetic resonance imaging, and magnetic resonance spectroscopy tests. Plasma sCD14 and sTNF-RII levels were elevated in subjects with cognitive impairment and in those with brain atrophy. Furthermore, both factors were correlated with spectroscopic choline:creatine ratios. These findings support the idea that peripheral immune responses are linked to cognitive dysfunction during advanced HIV-1 disease.

Insights into the neurodegenerative process of Alzheimer's disease: a role for mononuclear phagocyte-associated inflammation and neurotoxicity.

Since the first description of Alzheimers disease (AD) in 1907, significant progress was made into understanding disease pathophysiology. The enormous effort in AD research has translated into the discovery of genetic linkages for disease, into elucidating the structure and function of the etiologic β‐amyloid protein, and into unraveling the seemingly complex neuroimmunological cascade that affects neuronal dysfunction. Although effective therapies do not currently exist, many are being developed. We propose that the neuropathogenesis of AD, in measure, revolves around the immunological activation of glial cells, which in turn leads to alterations in inflammatory neurotoxin production, and ultimately to neuronal injury and death. Elucidating the mechanisms involved in such glial cell immune activation should provide valuable insights into understanding the disease process and in providing effective therapeutics to prevent and/or retard the devastating neurodegeneration that afflicts so many of our elderly. J. Leukoc. Biol. 65: 416–427; 1999.

The HIV-1 associated dementia complex: A metabolic encephalopathy fueled by viral replication in mononuclear phagocytes

HIV enters the brain soon after virus exposure but elicits profound neurological deficits in infected humans years later usually during progressive immunosuppression and the development of the acquired immune deficiency syndrome. The neurological disease complex associated with virus infection occurs in a large proportion of infected patients and is commonly referred to as HIV-1 associated dementia complex. The neuropathogenesis of central nervous system/viral infection revolves around mononuclear phagocytes (brain macrophage/microglial) infection and immune activation in brain. Macrophages secrete neurotoxic factors that elicit neuronal injury and inevitably death leading to the constellation of cognitive and motor impairments common during progressive disease. Neurotoxic factor production requires virus entry and replication, the evolution/selection of neurovirulent HIV-1 strains and the production of viral and cellular immune factors injurious to human neurons. Interestingly, neurological deficits, the HIV-1 associated neuropathology and viral replication disease are not always associated. This has led to the notion that viral replication induces the autocrine/paracrine production of cellular/viral factors leading to a metabolic encephalopathy. Anti-retroviral and anti-inflammatory therapies should prove increasingly beneficial for treatment and, ultimately, reversal of HIV-1 associated dementia complex in the affected human host.

Alcohol-induced blood-brain barrier dysfunction is mediated via inositol 1,4,5-triphosphate receptor (IP3R)-gated intracellular calcium release

The blood–brain barrier (BBB) formed by brain microvascular endothelial cells (BMVEC), pericytes and astrocytes controls the transport of ions, peptides and leukocytes in and out of the brain. Tight junctions (TJ) composed of TJ proteins (occludin, claudins and zonula occludens) ensure the structural integrity of the BMVEC monolayer. Neuropathologic studies indicated that the BBB was impaired in alcohol abusers; however, the underlying mechanism of BBB dysfunction remains elusive. Using primary human BMVEC, we previously demonstrated that oxidative stress induced by ethanol (EtOH) metabolism in BMVEC activated myosin light chain kinase (MLCK), resulting in the enhanced phosphorylation of either cytoskeletal or TJ proteins, and in BBB impairment. We proposed that EtOH metabolites stimulated inositol 1,4,5‐triphosphate receptor (IP3R)‐operated intracellular calcium (Ca2+) release, thereby causing the activation of MLCK in BMVEC. Indeed, treatment of primary human BMVEC with EtOH or its metabolites resulted in the increased expression of IP3R protein and IP3R‐gated intracellular Ca2+ release. These functional changes paralleled MLCK activation, phosphorylation of cytoskeletal/TJ proteins, loss of BBB integrity, and enhanced leukocyte migration across BMVEC monolayers. Inhibition of either EtOH metabolism or IP3R activation prevented BBB impairment. These findings suggest that EtOH metabolites act as signaling molecules for the activation of MLCK via the stimulation of IP3R‐gated intracellular Ca2+ release in BMVEC. These putative events can lead to BBB dysfunction in the setting of alcoholism, and to neuro‐inflammatory disorders promoting leukocyte migration across the BBB.