DHA modulates MANF and TREM2 abundance, enhances neurogenesis, reduces infarct size, and improves neurological function after experimental ischemic stroke

Abstract

Aims: Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a secretory neurotrophic factor protein that promotes repair after neuronal injury. The microglia cell surface receptor (triggering receptor expressed on myeloid cells-2; TREM2) regulates the production of pro-and antiinflammatory mediators after stroke. Here, we study MANF and TREM2 expression after middle cerebral artery occlusion (MCAo) and explore if docosahexaenoic acid (DHA) treatment exerts a potentiating effect. Methods: We used 2 hours of the MCAo model in rats and intravenously administered DHA or vehicle at 3 hours after the onset of MCAo. Neurobehavioral assessment was performed on days 1, 3, 7, and 14; MANF and TREM2 expression was measured by immunohistochemistry and Western blotting. Results: MANF was upregulated in neurons and astrocytes on days 1, 7, and 14, and TREM2 was expressed on macrophages in the ischemic penumbra and dentate gyrus (DG) on days 7 and 14. DHA improved neurobehavioral recovery, attenuated infarct size on days 7 and 14, increased MANF and decreased TREM2 expression in ischemic core, penumbra, DG, and enhanced neurogenesis on Day 14. Conclusion: MANF and TREM2 protein abundance is robustly increased after MCAo, and DHA treatment potentiated MANF abundance, decreased TREM2 expression, improved neurobehavioral recovery, reduced infarction, and provided enhanced neuroprotection.

Phagocytic microglia and macrophages in brain injury and repair

“…In intracerebral hemorrhage, TREM2 activation attenuates neuroinflammation and neuronal apoptosis by activating PI3K/Akt 96 . Taken together, microglial TREM2 may play a neuroprotective role in stroke and is a promising therapeutic target for the treatment of acute brain injuries 97,98 …”

Microglial phagocytosis and regulatory mechanisms after stroke

“…Numerous epidemiological studies and large-scale clinical trials have shown that the neuroprotective effects of dietary fatty acids after stroke may be related to their anti-inflammatory properties. 128 However, recent data also show that bioactive dietary fatty acids, such polyunsaturated fatty acids (PUFAs) or saturated fatty acids (SFAs), can cross the BBB to regulate microglia function, including phagocytosis. [124][125][126] Several in vitro studies in other CNS diseases have assessed the effect of PUFAs of the n-3 series on microglia phagocytosis and found that docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3) increased peptide ingestion by microglia in AD 129 and up-regulated gene expression of biomarkers associated with phagocytosis under myelin pathology.…”

UPR Responsive Genes Manf and Xbp1 in Stroke

“…Minor MANF expression was also found in astrocytes of the ischemic cortex but not in the normal healthy brain ( Shen et al, 2012 ). In a more recent study, Belayev et al found that docosahexaenoic acid increased MANF protein expression in neurons and astrocytes of the peri-ischemic region 24 h after transient MCAo in rats ( Belayev et al, 2020 ). Yang et al showed increased MANF expression in microglia/macrophages at the same time point after transient MCAo, and a further increase in MANF positive microglia/macrophages was seen when animals with stroke were pretreated with bone marrow mesenchymal stem cells ( Yang et al, 2020 ).…”

“…However, in the rat dMCAo model, the RTDL sequence is not needed for neuroprotection, implying that KDEL receptors do not have a significant role in mediating MANF’s neuroprotective effect on cerebral ischemia ( Matlik et al, 2015 ). Taking a different approach, Belayev et al used docosahexaenoic acid (DHA) to increase endogenous MANF protein expression after transient MCAo and observed neuroprotection and enhanced neurogenesis associated with DHA therapy ( Belayev et al, 2020 ). An important study on 18- to 20-month-old mice was conducted recently by Han et al and showed that the recombinant MANF protein given 2 h post-MCAo is also neuroprotective in the aging brain ( Han et al, 2021 ).…”

“…In previous studies, MANF protein expression was shown to be robustly increased after MCAo ( Belayev et al, 2020 ), and increasing MANF abundance could improve neurobehavioral recovery by means of promoting neuronal survival and modulation of innate immune cells ( Matlik et al, 2018 ). Also, application of the exogenous MANF protein can promote NPC differentiation in vitro as well as migration toward the infarct boundary in vivo ( Tseng et al, 2018 ).…”