MyD88 is a critical regulator of hematopoietic cell-mediated neuroprotection seen after stroke.

Abstract

Neuroinflammation is critical in the neural cell death seen in stroke. It has been shown that CNS and peripheral responses drive this neuroinflammatory response in the brain. The Toll-like receptors (TLRs) are important regulators of inflammation in response to both exogenous and endogenous stressors. Taking advantage of a downstream adapter molecule that controls the majority of TLR signalling, this study investigated the role of the TLR adaptor protein myeloid differentiation factor 88 (MyD88) in the control of CNS and peripheral inflammation. Reversible middle-cerebral artery occlusion was used as the model of stroke in vivo; in vitro primary cultured neurons and glia were subject to four hours of oxygen and glucose deprivation (OGD). Both in vitro and in vivo Myd88(-/-) animals or cells were compared with wild type (WT). We found that after stroke Myd88(-/-) animals have a larger infarct volume compared to WT animals. Interestingly, in vitro there was no difference between the survival of Myd88(-/-) and WT cells following OGD, suggesting that peripheral responses were influencing stroke outcome. We therefore generated bone marrow chimeras and found that Myd88(-/-) animals have a smaller stroke infarct than their radiation naive counterparts if their hematopoietic cells are WT. Furthermore, WT animals have a larger stroke than their radiation naive counterparts if the hematopoietic cells are Myd88(-/-) . We have demonstrated that MyD88-dependent signalling in the hematopoietic cell lineage reduces infarct size following stroke and that infiltrating cells to the site of neuroinflammation are neuroprotective following stroke.

• Authors: Catherine E Downes, Connie H Y Wong, Katya J Henley, Pedro L Guio-Aguilar, Moses Zhang, Robert Ates, Ashley Mansell, Benjamin T Kile, Peter J Crack
• Journal: PloS one (PLoS One) Vol. 8 Issue 3 Pg. e57948 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23483951 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Myeloid Differentiation Factor 88
• Neuroprotective Agents

Topics

• Animals
• Brain (metabolism, pathology)
• Brain Infarction (etiology, metabolism, pathology)
• Cell Movement
• Cell Survival
• Cells, Cultured
• Hematopoietic Stem Cells (metabolism)
• Infarction, Middle Cerebral Artery (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Myeloid Differentiation Factor 88 (metabolism)
• Neuroglia (metabolism, pathology)
• Neurons (metabolism, pathology)
• Neuroprotective Agents (metabolism)
• Signal Transduction
• Stroke (complications, metabolism)
• Treatment Outcome