interleukin-8 and Huntington-Disease

Studies on Huntington's disease (HD) demonstrated altered immune response in HD gene carriers. Using multiplexing immunoassay, we simultaneously investigated seven cytokines in secretomes of microglia and blood monocytes, cerebrospinal fluid (CSF) and serum collected from transgenic HD minipigs at pre-symptomatic disease stage. Decline in IFNα and IL-10 was observed in CSF and secretome of microglia whilst elevated IL-8 and IL-1β levels were secreted by microglia. Additionally, IL-8 was increased in serum. The proportion of mutant huntingtin in microglia may have causative impact on cytokine production. IFNα, IL-10, IL-8 and IL-1β represent promising biomarkers reflecting immuno-pathological mechanisms in porcine HD model.

Topics: Animals; Animals, Genetically Modified; Biomarkers; Calcium-Binding Proteins; Cells, Cultured; Central Nervous System; Cytokines; Disease Models, Animal; DNA-Binding Proteins; Gene Expression Regulation; Humans; Huntingtin Protein; Huntington Disease; Interferon-alpha; Interleukin-10; Interleukin-1beta; Interleukin-8; Lipopolysaccharides; Microfilament Proteins; Microglia; Monocytes; Nerve Tissue Proteins; Swine; Swine, Miniature

Previous studies have shown activation of the immune system and altered immune response in Huntington's disease (HD) gene carriers. Here, we hypothesized that peripheral and central immune responses could be concurrent pathophysiological events and represent a global innate immune response to the toxic effects of mutant huntingtin in HD gene carriers. We sought to investigate our hypothesis using [(11)C]PK11195 PET as a translocator protein (TSPO) marker of central microglial activation, together with assessment of peripheral plasma cytokine levels in a cohort of premanifest HD gene carriers who were more than a decade from predicted symptomatic conversion. Data were also compared to those from a group of healthy controls matched for age and gender. We found significantly increased peripheral plasma IL-1β levels in premanifest HD gene carriers compared to the group of normal controls (P=0.018). Premanifest HD gene carriers had increased TSPO levels in cortical, basal ganglia and thalamic brain regions (P<0.001). Increased microglial activation in somatosensory cortex correlated with higher plasma levels of IL-1β (rs=0.87, P=0.013), IL-6 (rs=0.85, P=0.013), IL-8 (rs=0.68, P=0.045) and TNF-α (rs=0.79; P=0.013). Our findings provide first in vivo evidence for an association between peripheral and central immune responses in premanifest HD gene carriers, and provide further supporting evidence for the role of immune dysfunction in the pathogenesis of HD.

Topics: Adult; Amides; Brain; Cytokines; Encephalitis; Female; Genetic Predisposition to Disease; Humans; Huntington Disease; Inflammation; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Interleukin-8; Isoquinolines; Male; Microglia; Middle Aged; Positron-Emission Tomography; Tumor Necrosis Factor-alpha

Neuroinflammation is a prominent feature of many neurodegenerative diseases, however, little is known about neuroinflammation in Huntington's disease. We used quantitative real time-PCR to compare the expression level of neuroinflammation-associated mediators in the striatum, cortex, and cerebellum from post-mortem Huntington's disease patient samples with controls. We found increased expression of several key inflammatory mediators, including CCL2 and IL-10, specifically in the striatum of Huntington's disease patients, the main area affected by this pathology. Remarkably, we also found upregulation of IL-6, IL-8, and MMP9, in the cortex and notably the cerebellum, a brain area commonly thought to be spared by Huntington's disease. Our data suggest that neuroinflammation is a prominent feature associated with Huntington's disease and may constitute a novel target for therapeutic intervention.

Topics: Adult; Aged; Cerebellum; Cerebral Cortex; Chemokine CCL2; Corpus Striatum; Female; Gene Expression; Humans; Huntington Disease; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Matrix Metalloproteinase 9; Middle Aged; RNA, Messenger; Tumor Necrosis Factor-alpha