Crosstalk between stressed brain cells: direct and indirect effects of ischemia and aglycemia on microglia

Abstract

Background: In cerebral ischemia, microglia have a dichotomous role in keeping the balance between pro-and anti-inflammatory mediators to avoid deleterious chronic inflammation and to leverage repair processes. Methods: We examined functional and inflammatory markers in primary rat microglia in vitro after oxygen-glucose deprivation (OGD) or glucose deprivation (aglycemia). We then investigated the preconditioning effect of OGD or aglycemia upon a subsequent strong inflammatory stimulus, here lipopolysaccharides (LPS). Moreover, an "in vitro brain model" of neurons and glia, differentiated from primary rat neural stem cells, was exposed to OGD or aglycemia. Conditioned medium (CM) of this neuronal/glial co-culture was then used to condition microglia, followed by LPS as a "second hit." Results: OGD or aglycemia at sublethal doses did not significantly affect microglia function, including the expression of inflammatory markers. However, preconditioning with either OGD or aglycemia led to a decreased pro-inflammatory response to a subsequent stimulus with LPS. Interestingly, the anti-inflammatory markers IGF-1 and IL-10 were additionally reduced after such preconditioning, while expression of CD206 remained unaffected. Treatment with CM from the neuronal/glial co-culture alone did not affect the expression of inflammatory markers in microglia. In contrast, treatment with CM increased the expression of both pro-and anti-inflammatory markers in microglia upon a second hit with LPS. Interestingly, this effect could be attenuated in microglia treated with CM from neuronal/glia co-cultures preconditioned with OGD or aglycemia.Conclusions: Data suggest specific and distinct microglia signatures in response to metabolic stress. While metabolic stress directly and indirectly applied to microglia did not mitigate their subsequent response to inflammation, preconditioning with metabolic stress factors such as OGD and aglycemia elicited a decreased inflammatory response to a subsequent inflammation stimulus.

Substrate Elasticity Exerts Functional Effects on Primary Microglia

“…Besides the static functional properties of microglia, recent studies highlight the importance of dynamic functional microglia states (Hamzei Taj et al, 2016;Vay et al, 2018;Rabenstein et al, 2020). In this respect, preconditioning of microglia, either pharmacologically or by a pathological stimulus, can modulate the successive microglia reaction upon further stimuli.…”

Gliotoxicity and Glioprotection: the Dual Role of Glial Cells

“…In astroglial cells, metabolic stress alters glutamate metabolism, mitochondrial activity/redox balance, inflammatory response, release of trophic factors, and different signaling pathways [ 34 – 36 ]. Glucose-related metabolic stress also affects microglia and oligodendrocytes/OPCs, promoting microglial activation and contributing to inflammatory and oxidative injuries to neurons [ 37 , 38 ]. Hypoglycemia inhibits oligodendrocyte development and differentiation, in addition to trigger apoptosis in OPCs [ 39 ], while glucose-oxygen deprivation causes intracellular lactate accumulation and acidosis [ 40 ].…”

Early‐life thermal stress mediates long‐term alterations in hypothalamic microglia

“…Moreover, there is a large variety of different receptors in the microglia, whose activation by immune signals, neurotransmitters, neuropeptides, hormones, lipid messengers and metabolites can drive the microglia toward beneficial functions (Verkhratsky et al, 2021). Recent publications suggest that microglia can play a protective role in stroke (McDonough & Weinstein, 2016) and metabolic stress, where preconditioning with metabolic stress factors such as oxygen–glucose deprivation and aglycemia elicited a decreased inflammatory response to subsequent LPS treatment (Rabenstein et al, 2020).…”