Neuroprotective effects of resident microglia following acute brain injury

Abstract

Microglia quickly react to various neurodegenerative processes by producing cytokines and eliminating cellular debris via phagocytosis. These events are also associated with an increased proliferation of microglia, which derive from resident progenitors and those present in the bone marrow. However, it is not clear whether the innate immune response by resident or newly differentiated microglia is beneficial or detrimental to the central nervous system. The aim of this study was to determine the impact of an altered immune response following acute excitotoxicity. Sodium nitroprusside (SNP) or kainic acid (KA) was administered in the brain of various groups of mice, and the extent of neurodegeneration, myelin damage, and inflammation was evaluated within a period of 2 weeks. We used synthetic glucocorticoid (GC), myeloid differentiation factor 88 (MyD88)-deficient mice to suppress nuclear factor kappaB (NF-kappaB) signaling and transgenic mice that express the thymidine kinase (TK) protein under the control of the CD11b promoter to determine the role of proliferating and infiltrating microglia in acute models of brain injury. Neurodegeneration was more extensive in GC-treated and MyD88-deficient mice, suggesting that NF-kappaB signaling and microglia activation are potent neuroprotective mechanisms in the presence of SNP. KA was also highly toxic to neurons of the amygdala in MyD88 knockout mice but not in their WT littermates. Although bone marrow-derived cells are clearly attracted to neurodegenerative areas, preventing their infiltration and differentiation did not affect the extent of SNP-related damage. These data indicate that MyD88/NF-kappaB signaling in resident non-proliferating microglia plays a critical role by restricting damage during acute excitotoxicity.

Lipopolysaccharide Sensitizes Neonatal Hypoxic-Ischemic Brain Injury in a MyD88-Dependent Manner

“…These data suggest that cerebral cytokine release is not necessarily associated with morphological signs of microglia activation and that microglial activation is not necessarily damaging. In support of these data, the shape of microglia can vary considerably from the resting phenotype to an active ameboid form, without increased cytokine production (45,46), whereas microglia have been shown to play both damaging and protective roles in CNS injury (47,48).…”

Acetylbritannilactone Modulates MicroRNA-155-Mediated Inflammatory Response in Ischemic Cerebral Tissues

“…Because previous studies have identified microglia as the major cellular mediator of injury (32,33) and the main source of IL-1β (34), we also tested the effect of OGD on the expression of proinflammatory cytokines in BV2 microglia cells. As expected, we found that the expressions of TNF-α and IL-1β in OGD-treated BV2 cells were similar to those seen in ischemic cerebral tissue.…”

Cortical Demyelination Is Prominent in the Murine Cuprizone Model and Is Strain-Dependent

“…20 However, other reports support the concept that proinflammatory cytokines produced by microglia are neuroprotective as shown by increased excitotoxicity in tumor necrosis factor-␣/interleukin-1␤ knockout mice. 21 Simard and Rivest 22 have shown that microglia activation and nuclear factor-B signaling are potent neuroprotective mechanisms after acute excitotoxicity. Moreover, there are several lines of evidence that microglia are also supportive for remyelination.…”