Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor

Abstract

Microglia and infiltrating leukocytes are considered major producers of tumor necrosis factor (TNF), which is a crucial player in cerebral ischemia and brain inflammation. We have identified a neuroprotective role for microglial-derived TNF in cerebral ischemia in mice. We show that cortical infarction and behavioral deficit are significantly exacerbated in TNF-knock-out (KO) mice compared with wild-type mice. By using in situ hybridization, immunohistochemistry, and green fluorescent protein bone marrow (BM)-chimeric mice, TNF was shown to be produced by microglia and infiltrating leukocytes. Additional analysis demonstrating that BM-chimeric TNF-KO mice grafted with wild-type BM cells developed larger infarcts than BM-chimeric wild-type mice grafted with TNF-KO BM cells provided evidence that the neuroprotective effect of TNF was attributable to microglial-not leukocyte-derived TNF. In addition, observation of increased infarction in TNF-p55 receptor (TNF-p55R)-KO mice compared with TNF-p75R and wild-type mice suggested that microglialderived TNF exerts neuroprotective effects through TNF-p55R. We finally report that TNF deficiency is associated with reduced microglial population size and Toll-like receptor 2 expression in unmanipulated brain, which might also influence the neuronal response to injury. Our results identify microglia and microglial-derived TNF as playing a key role in determining the survival of endangered neurons in cerebral ischemia.

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

“…Microglia activation and TNF release are associated with cell death and pathological inflammation, but they are also implicated in immune tolerance and brain repair. Removing TNF may not be fully beneficial, as this strategy has only had limited success 7,11-14 and TNF-deficient mice appear to have exacerbated cortical infarction and behavioural deficit 41 . One of the ARTICLE underlying reasons may be that a reduction in the homoeostatic levels of TNF may affect neuronal survival 6,12 .…”

Inflammatory mechanisms involved in brain injury following cardiac arrest and cardiopulmonary resuscitation

“…CA/CPR-induced neurological damage is a progressive process that can develop over a long time following the initial injury (15). As aforementioned, strong evidence now exists to suggest that neuroinflammation continues for days and months, and contributes to the neurological damage that ultimately determines the impaired recovery following CA and CPR (16). This suggests that the neuroprotective anti-inflammatory treatments discussed in the following are promising strategies for CA and resuscitation intervention.…”

“…Despite a more comprehensive understanding regarding the mechanisms of cerebral injury, currently no clinically proven pharmacological therapy data against cerebral I/R damage during CA and CPR are available (15). Increasing evidence reveals that suppressing the inflammatory process facilitates neuroprotection and has potential for use in the clinical treatment of cerebral I/R damage regarding CA (16).…”

The role of the immune system in central nervous system plasticity after acute injury

“…In particular, TNF-α play a beneficial role in neurogenesis after ischemic injury, probably acting via its receptor TNF-R2, promoting the survival of strokegenerated hippocampal and striatal neurons (Heldmann et al, 2005). Interestingly, it has been shown that TNFα knockout mice have a 50% increase in the final ischemic damage (Lambertsen et al, 2009). Microglial activation in the perilesional area might also positively regulate post-stroke neurogenesis by increasing the expression of the neuroprotective mediator IGF-1 in the SVZ (Thored et al, 2009).…”