Dyslipidemic Diet Induces Mobilization of Peripheral Neutrophils and Monocytes That Exacerbate Hemorrhagic Brain Injury and Neuroinflammation

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is a common liver condition characterized by a significant accumulation of lipids in the liver without excessive alcohol consumption. Accumulating evidence suggests a significantly increased risk of intracerebral hemorrhage (ICH) in NAFLD patients. However, it remains poorly understood whether and how NAFLD affects the outcome of hemorrhagic brain injury. Here, we examined the effects of diet-induce NAFLD on ICH injury and neuroinflammation in mice. Methods: NAFLD was induced in C57BL/6 mice by feeding with a methionine-choline deficient (MCD) diet for 4 weeks. Collagenase and autologous blood models were used to evaluate the effects of NAFLD on ICH injury and neuroinflammation. Results: MCD diet for 4 weeks induces NAFLD and hyperlipidemia in mice. Mice receiving the MCD diet have aggravated neurological deficits and brain edema after ICH. The augmentation of ICH injury was accompanied by brain infiltration of neutrophils and monocytes and increased production of pro-inflammatory factors. Before ICH, MCD diet-induced mobilization of neutrophils and monocytes in the periphery. Notably, the detrimental effects of NAFLD on ICH injury was ablated in mice receiving antibody depletion of neutrophils and monocytes. Conclusions: These results suggest that NAFLD exacerbates neuroinflammation and ICH injury.

Neutrophil reverse migration from liver fuels neutrophilic inflammation to tissue injury in Nonalcoholic Steatohepatitis

“…Similarly, exacerbated neuroinflammation and intracerebral hemorrhage injury was previously observed in a mouse model of NAFLD 56 . Moreover, recruited neutrophils to tissue injury migrate at a higher speed in NASH larvae.…”

Cognitive Dysfunction in Non-Alcoholic Fatty Liver Disease—Current Knowledge, Mechanisms and Perspectives

“…Collectively, these studies indicate that NASH is associated with impaired spatial learning and memory as well as depression-like behaviour, and that these neurobehavioral changes are accompanied by microglia activation and increased release of proinflammatory cytokines in brain tissue [ 61 , 62 , 63 ]. Furthermore, the induction of NAFLD in models of Alzheimer’s disease (AD) and haemorrhagic brain injury exacerbates cognitive impairment and neuroinflammation [ 64 , 65 ]. In human NAFLD, chronic neuroinflammation was suggested by Balzano et al, who studied post-mortem cerebellums of NASH patients and found neuronal loss, lymphocyte infiltration and increased activation of microglia and astrocytes, as compared with control autopsies from subjects without liver or brain disease [ 66 , 67 ].…”

Inhibition of exosome release augments neuroinflammation following intracerebral hemorrhage

“…Modified Neurological Severity Score (mNSS), foot‐fault test and corner‐turning test were conducted to evaluate the functional outcome of mice at days 1 and 3 after ICH by two investigators blinded to the mouse groups as previously described 23,24 …”

“…Mice were given GW4869 solution at a dose of 2.5μg/g or equal volume of DMSO (3.75%) by intraperitoneal injection at days 0 and 2 after ICH. In mice subjected to Gr‐1 + cell depletion, 250 µg anti‐mouse Gr‐1 monoclonal antibody (MAb‐RB6‐8C5, BioXcell, West Lebanon, NH, USA) was given to each mouse by intraperitoneal injection one day before and one day after ICH surgery as we previously reported 23 …”

“…The procedure we harvested single cells from spleen, brain, and blood samples as we previously described. 23,26 All antibodies were purchased from Biolegend (San Diego, CA, USA). The following antibodies were used: CD45 (30-F11), CD11b (M1/70), CD3 (145-2C11), CD4 (GK1.4), CD8 (53-6.7), NK1.1 (PK136), CD19 (1D3), Ly6G (1A8), Ly6C (ER-MP20), CD63 (NVG-2), and CD81 (Eat-2).…”