Abstract
BackgroundNeuroinflammation plays a critical role in the onset and development of neurodegeneration disorders such as Parkinson’s disease. The immune activities of the central nervous system are profoundly affected by peripheral immune activities. Immune tolerance refers to the unresponsiveness of the immune system to continuous or repeated stimulation to avoid excessive inflammation and unnecessary by-stander injury in the face of continuous antigen threat. It has been proved that the immune tolerance could suppress the development of various peripheral inflammation-related diseases. However, the role of immune tolerance in neuroinflammation and neurodegenerative diseases was not clear.MethodsRats were injected with repeated low-dose lipopolysaccharide (LPS, 0.3 mg/kg) intraperitoneally for 4 days to induce peripheral immune tolerance. Neuroinflammation was produced using intracranial LPS (15 μg) injection. Inflammation cytokines were measured using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). Microglial activation were measured using immunostaining of Iba-1 and ED-1. Dopaminergic neuronal damage was evaluated using immunochemistry staining and stereological counting of TH-positive neurons. Behavioral impairment was evaluated using amphetamine-induced rotational behavioral assessment.ResultsCompared with the non-immune tolerated animals, pre-treatment of peripheral immune tolerance significantly decreased the production of inflammatory cytokines, suppressed the microglial activation, and increased the number of dopaminergic neuronal survival in the substantia nigra.ConclusionsOur results indicated that peripheral immune tolerance attenuated neuroinflammation and inhibited neuroinflammation-induced dopaminergic neuronal death.
Highlights
Neuroinflammation plays a critical role in the onset and development of neurodegeneration disorders such as Parkinson’s disease
Repeated low-dose LPS intraperitoneal injection-induced endotoxic tolerance of peripheral blood monocytes (PBM) To test whether endotoxic tolerance could be induced by repeated low-dose LPS intraperitoneal injection, Tumor necrosis factor-α (TNF-α) and IL-1β secreted by PBM and toll-like receptor 4 (TLR4) expressed in PBM were quantified post to a single-dose LPS (100 ng/ml) administration
Repeated low-dose LPS intraperitoneal injection was not sufficient to cause inflammation in the substantia nigra (SN) To verify that the pre-treatment with repeated low-dose LPS intraperitoneal injection was not sufficient to cause inflammation in the SN, we investigated the levels of pre-inflammatory cytokines (TNF-α and IL-1β) and the expression of Iba-1 in the right SN of rats from the LPS (i.p.) group at 1, 7, 14, and 28 days post to the last peripheral LPS injection
Summary
Neuroinflammation plays a critical role in the onset and development of neurodegeneration disorders such as Parkinson’s disease. It has been proved that the immune tolerance could suppress the development of various peripheral inflammation-related diseases. Characteristic features of neuroinflammation include the activation of glial cells and a series of inflammatory mediators including proinflammatory cytokines, chemokines, reactive oxygen species, and nitric oxide [2]. These elements have been proved to involve in the development of neuronal degeneration [3]. Long-term use of non-steroidal anti-inflammatory drugs could decrease the incidence of PD [7, 8] These results suggest that the neuroinflammation can be strongly influenced by the peripheral inflammation
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