Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice.

OBJECTIVE: To investigate miR-155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS). METHODS: NanoString microRNA, microglia and immune gene profiles, protein mass spectrometry, and RNA-seq analyses were measured in spinal cord microglia, splenic monocytes, and spinal cord tissue from SOD1 mice and in spinal cord tissue of familial and sporadic ALS. miR-155 was targeted by genetic ablation or by peripheral or centrally administered anti-miR-155 inhibitor in SOD1 mice. RESULTS: In SOD1 mice, we found loss of the molecular signature that characterizes homeostatic microglia and increased expression of miR-155. There was loss of the microglial molecules P2ry12, Tmem119, Olfml3, transcription factors Egr1, Atf3, Jun, Fos, and Mafb, and the upstream regulators Csf1r, Tgfb1, and Tgfbr1, which are essential for microglial survival. Microglia biological functions were suppressed including phagocytosis. Genetic ablation of miR-155 increased survival in SOD1 mice by 51 days in females and 27 days in males and restored the abnormal microglia and monocyte molecular signatures. Disease severity in SOD1 males was associated with early upregulation of inflammatory genes, including Apoe in microglia. Treatment of adult microglia with apolipoprotein E suppressed the M0-homeostatic unique microglia signature and induced an M1-like phenotype. miR-155 expression was increased in the spinal cord of both familial and sporadic ALS. Dysregulated proteins that we identified in human ALS spinal cord were restored in SOD1(G93A) /miR-155(-/-) mice. Intraventricular anti-miR-155 treatment derepressed microglial miR-155 targeted genes, and peripheral anti-miR-155 treatment prolonged survival. INTERPRETATION: We found overexpression of miR-155 in the SOD1 mouse and in both sporadic and familial human ALS. Targeting miR-155 in SOD1 mice restores dysfunctional microglia and ameliorates disease. These findings identify miR-155 as a therapeutic target for the treatment of ALS.

Agricultural dust exposure and respiratory symptoms among California farm operators.

OBJECTIVE: To study whether dust exposure in California agriculture is a risk factor for respiratory symptoms. METHODS: A population-based survey of 1947 California farmers collected respiratory symptoms, occupational and personal exposures. Associations between dust and respiratory symptoms were assessed by logistic regression models. RESULTS: The prevalence of persistent wheeze was 8.6%, chronic bronchitis 3.8%, chronic cough 4.2%, and asthma 7.8%. Persistent wheeze was independently associated with dust in a dose-response fashion odds ratio, 1.2 (95% confidence interval[CI]=0.8-2.0) and 1.8 (95% CI=1.1-3.2) for low and high time in dust. A borderline significant association between chronic bronchitis and dust exposure was found. Asthma was associated with keeping livestock, but not with dust exposure. CONCLUSIONS: Occupational dust exposure among California farmers, only one third of whom tended animals, was independently associated with chronic respiratory symptoms.

Personal exposures to inorganic and organic dust in manual harvest of California citrus and table grapes.

The aim of this study was to determine characteristics of personal exposure to inorganic and organic dust during manual harvest operations of California citrus and table grapes. Personal exposures to inhalable dust and respirable dust were measured five times over a 4-month period of harvesting season. We analyzed components of the dust samples for mineralogy, respirable quartz, endotoxin, and total and culturable microorganisms. Workers manually harvesting were exposed to a complex mixture of inorganic and organic dust. Exposures for citrus harvest had geometric means of 39.7 mg/m(3) for inhalable dust and 1.14 mg/m(3) for respirable dust. These exposures were significantly higher than those for table grape operations and exceeded the threshold limit value for inhalable dust and respirable quartz. Exposures for table grape operations were lower than the threshold limit value, except inhalable dust exposure during leaf pulling. Considered independently, exposures to inhalable dust and respirable quartz in citrus harvest may be high enough to cause respiratory health effects. The degree of vigorous contact with foliage appeared to be a significant determining factor of exposures in manual harvesting.