Neuronal MCP‐1 Mediates Microglia Recruitment and Neurodegeneration Induced by the Mild Impairment of Oxidative Metabolism

Abstract

Chemokines are implicated in the neuroinflammation of several chronic neurodegenerative disorders. However, the precise role of chemokines in neurodegeneration is unknown. Thiamine deficiency (TD) causes abnormal oxidative metabolism in the brain as well as a well-defined microglia activation and neurodegeneration in the submedial thalamus nucleus (SmTN), which are common features of neurodegenerative diseases. We evaluated the role of chemokines in neurodegeneration and the underlying mechanism in a TD model. Among the chemokines examined, TD selectively induced neuronal expression of monocyte chemoattractant protein-1 (MCP-1) in the SmTN prior to microglia activation and neurodegeneration. The conditioned medium collected from TD-induced neurons caused microglia activation. With a neuron/microglia co-culture system, we showed that MCP-1-induced neurotoxicity required the presence of microglia and exogenous MCP-1 was able to activate microglia and stimulated microglia to produce cytokines. A MCP-1 neutralizing antibody inhibited MCP-1-induced microglia activation and neuronal death in culture and in the thalamus. MCP-1 knock-out mice were resistant to TD-induced neuronal death in SmTN. TD selectively induced the accumulation of reactive oxygen species in neurons, and antioxidants blocked TD-induced MCP-1 expression. Together, our results indicated an induction of neuronal MCP-1 during mild impairment of oxidative metabolism caused microglia recruitment/activation, which exacerbated neurodegeneration.

Cerebrolysin protects against rotenone-induced oxidative stress and neurodegeneration

“…MCP-1 causes microglia recruitment/activation to produce cytokines and exacerbates neurodegeneration. 96 Our data showed that the rotenone-induced elevation in striatal MCP-1 decreased after treatment with cerebrolysin. Cerebrolysin, thus, might exert its neuroprotective action, at least in part, by preventing the release of MCP-1 during inflammation.…”

Inhibition of ASK1-p38 pathway prevents neural cell death following optic nerve injury

“…Consistently, neural MCP-1 in the brain has been reported to mediate microglia recruitment and activation that exacerbates neurodegeneration. 22 Lack of this upregulation in ASK1 KO mice suggested that the microglia were not navigated effectively to the injury site in these mice. Pharmacological inactivation of ASK1 or p38 suppressed LPS-induced TNFa and LPS/TNFa-induced iNOS productions in microglia (Figure 7).…”

Retracted: Anti‐inflammatory properties of tianeptine on lipopolysaccharide‐induced changes in microglial cells involve toll‐like receptor‐related pathways

“…Increasing evidence indicates that microglia, the resident immune cells in the central nervous system (CNS), may be considered the main mediators of inflammation-associated disorders. These cells manage the innate and adaptive immune responses in various pathological processes including brain trauma, ischemia, stroke and infections, as well as during CNS repair (Graeber and Streit 2010;Yang et al 2011). It has been observed that active microglia can clear Received September 29, 2015; revised manuscript received November 16, 2015; accepted November 17, 2015.…”