Malibatol A regulates microglia M1/M2 polarization in experimental stroke in a PPARγ-dependent manner

Pan, Jie; Jin, Jiali; Ge, Hui‐Ming; Yin, Kang; Chen, Xiang; Han, Lijuan; Chen, Yan; Lai, Qi; Li, Xiaoxi; Xu, Yun

doi:10.1186/s12974-015-0270-3

Cited by 170 publications

(97 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, microglia can assume either of the 2 well‐established phenotypes: one is a detrimental form (M1) and the other is a beneficial phenotype (M2) (10, 11). As previous studies have verified, both phenotypes of microglia exist during ischemic stroke (12). However, the vulnerable brain environment favors M1 microglia, leading to neurologic deficits (13, 14).…”

supporting

confidence: 66%

mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type

et al. 2016

View full text Add to dashboard Cite

Inflammatory factors secreted by microglia play an important role in focal ischemic stroke. The mammalian target of rapamycin (mTOR) pathway is a known regulator of immune responses, but the role that mTORC1 signaling plays in poststroke neuroinflammation is not clear. To explore the relationship between microglial action in the mTORC1 pathway and the impact on stroke, we administered the mTORC1 inhibitors sirolimus and everolimus to mice. Presumably, disrupting the mTORC1 pathway after focal ischemic stroke should clarify the subsequent activity of microglia. For that purpose, we generated mice deficient in the regulatory associated protein of mTOR (Raptor) in microglia, whose mTORC1 signaling was blocked, by crossing Raptor loxed (Raptor) mice with CX3CR1 mice, which express Cre recombinase under the control of the CX3C chemokine receptor 1 promoter. mTORC1 blockade reduced lesion size, improved motor function, dramatically decreased production of proinflammatory cytokines and chemokines, and reduced the number of M1 type microglia. Thus, mTORC1 blockade apparently attenuated behavioral deficits and poststroke inflammation after middle cerebral artery occlusion by preventing microglia polarization toward the M1 type.-Li, D., Wang, C., Yao, Y., Chen, L., Liu, G., Zhang, R., Liu, Q., Shi, F.-D., Hao, J. mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type.

show abstract

supporting

confidence: 66%

mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Stroke reinforced M1 microglia reactions and decreased M2 microglia markers, whereas TH counteracts these effects. After stroke induction in rodents, an increased M1 polarization contributes to the inflammatory cascade and propagated cell death beyond the initial ischemic region (Pan et al, 2015; Won et al, 2015). Mice that lack appropriate signals for M2 induction have worse outcomes after cerebral ischemia.…”

Section: Discussionmentioning

confidence: 99%

Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice

Lee

Wei

Cao

et al. 2016

Neurobiology of Disease

116

View full text Add to dashboard Cite

Stroke is a leading threat to human life and health in the US and around the globe, while very few effective treatments are available for stroke patients. Preclinical and clinical studies have shown that therapeutic hypothermia (TH) is a potential treatment for stroke. Using novel neurotensin receptor 1 (NTR1) agonists, we have demonstrated pharmacologically induced hypothermia and protective effects against brain damages after ischemic stroke, hemorrhage stroke, and traumatic brain injury (TBI) in rodent models. To further characterize the mechanism of TH-induced brain protection, we examined the effect of TH (at ±33°C for 6 hrs) induced by the NTR1 agonist HPI-201 or physical (ice/cold air) cooling on inflammatory responses after ischemic stroke in mice and oxygen glucose deprivation (OGD) in cortical neuronal cultures. Seven days after focal cortical ischemia, microglia activation in the penumbra reached a peak level, which was significantly attenuated by TH treatments commenced 30 min after stroke. The TH treatment decreased the expression of M1 type reactive factors including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-12, IL-23, and inducible nitric oxide synthase (iNOS) measured by RT-PCR and Western blot analyses. Meanwhile, TH treatments increased the expression of M2 type reactive factors including IL-10, Fizz1, Ym1, and arginase-1. In the ischemic brain and in cortical neuronal/BV2 microglia cultures subjected to OGD, TH attenuated the expression of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α), two key chemokines in the regulation of microglia activation and infiltration. Consistently, physical cooling during OGD significantly decreased microglia migration 16 hrs after OGD. Finally, TH improved functional recovery at 1, 3, and 7 days after stroke. This study reveals the first evidence for hypothermia mediated regulation on inflammatory factor expression, microglia polarization, migration and indicates that the anti-inflammatory effect is an important mechanism underlying the brain protective effects of a TH therapy.

show abstract

“…Microglia can also be activated by IL4/IL3 to the M2 polarization state, which produces anti-inflammatory mediators (IL-10, transforming growth factor beta (TGFβ), and glucocorticoids) [54, 55]. M2 microglia are also interpreted to be nerve repair cells, as they secrete anti-inflammatory factors and upregulate neuroprotective factors in CNS disease [56]. Because M1 and M2 microglia secrete different factors, several markers have been used to distinguish the two phenotypes.…”

Section: Microgliamentioning

confidence: 99%

Microglial Polarization and Inflammatory Mediators After Intracerebral Hemorrhage

et al. 2016

View full text Add to dashboard Cite

Intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality and morbidity. When a diseased artery within the brain bursts, expansion and absorption of the resulting hematoma trigger a series of reactions that cause primary and secondary brain injury. Microglia are extremely important for removing the hematoma and clearing debris, but they are also a source of ongoing inflammation. This article discusses the role of microglial activation/polarization and related inflammatory mediators, such as Toll-like receptor 4, matrix metalloproteinases, high-mobility group protein box-1, nuclear factor erythroid 2-related factor 2, heme oxygenase, and iron, in secondary injury after ICH and highlights the potential targets for ICH treatment.

show abstract

Malibatol A regulates microglia M1/M2 polarization in experimental stroke in a PPARγ-dependent manner

Cited by 170 publications

References 38 publications

mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type

mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type

Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice

Microglial Polarization and Inflammatory Mediators After Intracerebral Hemorrhage

Contact Info

Product

Resources

About