Traumatic brain injury (TBI) and spinal cord injury (SCI) are pathological events that lead to neuropathological conditions which have in consequence the initiation of pro‐inflammatory cytokine ...production. Neuroinflammation plays a key role in the secondary phase of both TBI and SCI after initial cell death. Activation of cytoplasmic inflammasome complexes is regarded as the essential step of neuroinflammation and a key trigger for neuronal death called pyroptosis. Inflammasome complexes are involved in activation of caspase‐1 which catalyzes the cleavage of pro‐interleukins into their active forms (including interleukin‐18 IL‐18 and IL‐1β). The focus of this article is to discuss the time‐course and regulation of inflammasome assembly and activation during TBI and SCI and their targeting in designing therapeutic approaches. We particularly focus on the inflammasomes NLRP1 and NLRP3 which play a pivotal function during TBI and SCI in the central nervous system (CNS).
Neuroinflammation plays a key role in the secondary phase of both TBI and SCI after initial cell death. Activation of cytoplasmic inflammasome complexes is regarded as the essential step of neuroinflammation and a key trigger for neuronal death called pyroptosis. The NLRP1 and NLRP3 inflammasome complexs are possibly the dominant types of inflammasomes activated in the TBI and SCI.
Microglia are the resident immune cells in the CNS, which survey the brain parenchyma for pathogens, initiate inflammatory responses, secrete inflammatory mediators, and phagocyte debris. Besides, ...they play a role in the regulation of brain ion homeostasis and in pruning synaptic contacts and thereby modulating neural networks. More recent work shows that microglia are embedded in brain response related to stress phenomena, the development of major depressive disorders, and pain-associated neural processing. The microglia phenotype varies between activated-toxic-neuroinflammatory to non-activated-protective-tissue remodeling, depending on the challenges and regulatory signals. Increased inflammatory reactions result from brain damage, such as stroke, encephalitis, as well as chronic dysfunctions, including stress and pain. The dimension of damage/toxic stimuli defines the amplitude of inflammation, ranging from an on-off event to low but continuous simmering to uncontrollable. Pain, either acute or chronic, involves inflammasome activation at the point of origin, the different relay stations, and the sensory and processing cortical areas. This short review aimed at identifying a sinister role of the microglia-inflammasome platform for the development and perpetuation of acute and chronic central pain and its association with changes in CNS physiology.
CNS ischemia results in locally confined and rapid tissue damage accompanied by a loss of neurons and their circuits. Early and time-delayed inflammatory responses are critical variables determining ...the extent of neural disintegration and regeneration. Inflammasomes are vital effectors in innate immunity. Their activation in brain-intrinsic immune cells contributes to ischemia-related brain damage. The steroids 17β-estradiol (E2) and progesterone (P) are neuroprotective and anti-inflammatory. Using a transient focal rat ischemic model, we evaluated the time response of different inflammasomes in the peri-infarct zone from the early to late phases after poststroke ischemia. We show that the different inflammasome complexes reveal a specific time-oriented sequential expression pattern with a maximum at approximately 24 h after the infarct. Within the limits of antibody availability, immunofluorescence labeling demonstrated that microglia and neurons are major sources of the locally activated inflammasomes NOD-like receptor protein-3 (NLRP3) and associated speck-like protein (ASC), respectively. E2 and P given for 24 h immediately after ischemia onset reduced hypoxia-induced mRNA expression of the inflammasomes NLRC4, AIM2 and ASC, and decreased the protein levels of ASC and NLRP3. In addition, mRNA protein levels of the cytokines interleukin-1β (IL1β), IL18 and TNFα were reduced by the steroids. The findings provide for the first time a detailed flow chart of hypoxia-driven inflammasome regulation in the peri-infarct cerebral cortex. Further, we demonstrate that E2 and P alleviate the expression of certain inflammasome components, sometimes in a hormone-specific way. Besides directly regulating other cellular neuroprotective pathways, the control of inflammasomes by these steroids might contribute to its neuroprotective potency.
Acute ischemic stroke (AIS) is a devastating neurological condition with a lack of neuroprotective therapeutic options, despite the reperfusion modalities thrombolysis and thrombectomy. Post-ischemic ...brain damage is aggravated by an excessive inflammatory cascade involving the activation and regulation of the pro-inflammatory cytokines IL-1β and IL-18 by inflammasomes. However, the role of AIM2 and NLRC4 inflammasomes and the influence of the neuroprotective steroids 17β-estradiol (E2) and progesterone (P) on their regulation after ischemic stroke have not yet been conclusively elucidated. To address the latter, we subjected a total of 65 rats to 1 h of transient Middle Cerebral Artery occlusion (tMCAO) followed by a reperfusion period of 72 h. Moreover, we evaluated the expression and regulation of AIM2 and NLRC4 in glial single-cell cultures (astroglia and microglia) after oxygen-glucose deprivation (OGD). The administration of E2 and P decreased both infarct sizes and neurological impairments after cerebral ischemia in rats. We detected a time-dependent elevation of gene and protein levels (Western Blot/immunohistochemistry) of the AIM2 and NLRC4 inflammasomes in the post-ischemic brains. E2 or P selectively mitigated the stroke-induced increase of AIM2 and NLRC4. While both inflammasomes seemed to be exclusively abundant in neurons under physiological and ischemic conditions in vivo, single-cell cultures of cortical astrocytes and microglia equally expressed both inflammasomes. In line with the in vivo data, E and P selectively reduced AIM2 and NLRC4 in primary cortical astrocytes and microglial cells after OGD. In conclusion, the post-ischemic elevation of AIM2 and NLRC4 and their down-regulation by E2 and P may shed more light on the anti-inflammatory effects of both gonadal hormones after stroke.
Astrocytes are the most abundant cell type in the brain and crucial to ensure the metabolic supply of neurons and their synapse formation. Overnutrition as present in patients suffering from obesity ...causes astrogliosis in the hypothalamus. Other diseases accompanied by malnutrition appear to have an impact on the brain and astrocyte function. In the eating disorder anorexia nervosa (AN), patients suffer from undernutrition and develop volume reductions of the cerebral cortex, associated with reduced astrocyte proliferation and cell count. Although an effect on astrocytes and their function has already been shown for overnutrition, their role in long-term undernutrition remains unclear. The present study used primary rat cerebral cortex astrocytes to investigate their response to chronic glucose starvation. Cells were grown with a medium containing a reduced glucose concentration (2 mM) for 15 days. Long-term glucose starvation increased the expression of a subset of pro-inflammatory genes and shifted the primary astrocyte population to the pro-inflammatory A1-like phenotype. Moreover, genes encoding for proteins involved in the unfolded protein response were elevated. Our findings demonstrate that astrocytes under chronic glucose starvation respond with an inflammatory reaction
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With respect to the multiple functions of astrocytes, an association between elevated inflammatory responses due to chronic starvation and alterations found in the brain of patients suffering from undernutrition seems possible.
Neuroprotection by estrogen in the CNS is well-documented and comprises the intricate regulation of cell-cell communication between neurons and supportive non-neuronal glial cells. It is assumed that ...these interactions are essential for cell survival under pathological and toxic conditions by regulating the allocation of trophic molecules, e.g., growth factors, controlling relevant intracellular anti-apoptotic and death cascades, and attenuating inflammatory processes. Malfunction and disturbance of mitochondria are doubtlessly associated with brain cell degeneration during neurotoxic and neurodegenerative processes. Estrogen has been documented as protective agent in the brain by stimulating growth factor supply and cell-intrinsic pro-/anti-apoptotic signaling pathways. In recent years, an additional estrogen-dependent safe-guarding strategy comes into the focus of neuronal protection. The mitochondrial compartment appears to be regulated by estrogen at the level of ATP and reactive oxygen species production as well as under a structural-functional viewpoint. In the present article, we would like to highlight recent data which demonstrate that sex steroids can directly and indirectly interfere with mitochondrial properties via non-nuclear, presumably mitochondria-intrinsic and nuclear signaling mechanisms. This enables mitochondria to cope with pathological processes and provide stabile local energy homeostasis and an anti-apoptotic base setting in the brain which, in turn, is a prerequisite for neuronal survival.
Abstract Synthetic and natural estrogens as well as progestins modulate neuronal development and activity. Neurons and glia are endowed with high-affinity steroid receptors. Besides regulating brain ...physiology, both steroids conciliate neuroprotection against toxicity and neurodegeneration. The majority of data derive from in vitro studies, although more recently, animal models have proven the efficaciousness of steroids as neuroprotective factors. Indications for a safeguarding role also emerge from first clinical trials. Gender-specific prevalence of degenerative disorders might be associated with the loss of hormonal activity or steroid malfunctions. Our studies and evidence from the literature support the view that steroids attenuate neuroinflammation by reducing the pro-inflammatory property of astrocytes. This effect appears variable depending on the brain region and toxic condition. Both hormones can individually mediate protection, but they are more effective in cooperation. A second research line, using an animal model for multiple sclerosis, provides evidence that steroids achieve remyelination after demyelination. The underlying cellular mechanisms involve interactions with astroglia, insulin-like growth factor-1 responses, and the recruitment of oligodendrocytes.
Demyelination of the central nervous system (CNS) has been associated to reactive microglia in neurodegenerative disorders, such as multiple sclerosis (MS). The M1 microglia phenotype plays a ...pro-inflammatory role while M2 is involved in anti-inflammatory processes in the brain. In this study, CPZ-induced demyelination mouse model was used to investigate the effect of progesterone (PRO) therapy on microglia activation and neuro-inflammation. Results showed that progesterone therapy (CPZ+PRO) decreased neurological behavioral deficits, as demonstrated by significantly decreased escape latencies, in comparison to CPZ mice. In addition, CPZ+PRO caused a significant reduction in the mRNA expression levels of M1-markers (iNOS, CD86, MHC-II and TNF-α) in the corpus callosum region, whereas the expression of M2-markers (Trem-2, CD206, Arg-1 and TGF-β) was significantly increased, in comparison to CPZ mice. Moreover, CPZ+PRO resulted in a significant decrease in the number of iNOS+ and Iba-1+/iNOS+ cells (M1), whereas TREM-2+ and Iba-1+/TREM-2+ cells (M2) significantly increased, in comparison to CPZ group. Furthermore, CPZ+PRO caused a significant decrease in mRNA and protein expression levels of NLRP3 and IL-18 (~2-fold), in comparison to the CPZ group. Finally, CPZ+PRO therapy was accompanied with reduced levels of demyelination, compared to CPZ, as confirmed by immunofluorescence to myelin basic protein (MBP) and Luxol Fast Blue (LFB) staining, as well as transmission electron microscopy (TEM) analysis. In summary, we reported for the first time that PRO therapy causes polarization of M2 microglia, attenuation of M1 phenotype, and suppression of NLRP3 inflammasome in a CPZ-induced demyelination model of MS.
•Progesterone, a sex hormone, suppresses the M1- microglia phenotype markers (CD86, iNOS, TNF-α and MHC-II) in cuprizone demyelinated mice.•Progesterone, increases the M2- microglia phenotype markers (CD206, Arg-1, TGF-β and Trem-2) in cuprizone demyelinated mice.•Progesterone therapy downregulates either the gene or protein expression of NLRP3 inflammasome and its downstream product of IL-18.•Progesterone therapy resulted in a significant decrease in the number of iNOS+ and Iba-1+/iNOS+ cells (M1-microglia), whereas TREM-2+ and Iba-1+/TREM-2+ cells (M2-microglia) significantly increased, in comparison to untreated mice.•Progesterone therapy stimulates the remyelination.
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