Brain inflammasomes in stroke and depressive disorders: regulation by estrogen

Abstract

Neuroinflammation is a devastating pathophysiological process which ends up in brain damage and neuronal death. Pathogens, cell fragments and cellular dysfunction trigger inflammatory responses. Irrespective of the cause, inflammasomes are key intracellular multiprotein signaling platforms which sense neuropathological conditions. The activation of inflammasomes leads to the auto-proteolytic cleavage of caspase-1, resulting in the proteolysis of the pro-inflammatory cytokines interleukin (IL)1beta and IL18 into their bioactive forms. It also initiates pyroptosis, a type of cell death. The two cytokines contribute to the pathogenesis in acute and chronic brain diseases and also play a central role in human aging and psychiatric disorders.

Sex steroids, in particular estrogens, are well-described neuroprotective agents in the central nervous system. Estrogens improve the functional outcome after ischemia and traumatic brain injury, reduce neuronal death in Parkinson′s and Alzheimer′s disease as well as in amyotrophic lateral sclerosis, attenuate glutamate excitotoxicity and formation of radical oxygen species, and lesson edema spreading after damage. Moreover, estrogens alleviate menopause-related depressive symptoms and have a positive influence on depressive disorders probably by influencing growth factor production and serotonergic brain circuits. Recent evidence also suggests that inflammasome signaling affects anxiety- and depressive-like behavior and that estrogen ameliorates depression-like behavior through suppression of inflammasomes.

In this article, we highlight the most recent findings demonstrating that estrogens selectively suppress the activation of the neuroinflammatory cascade in the brain in acute and chronic brain disease models. Further, we aim at describing putative regulatory signaling pathways involved in the control of inflammasomes. Finally, we will consider that psychiatric disorders such as depression also contain an inflammatory component which could be modulated by estrogen.

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