Gestational Hypothyroxinemia Imprints a Switch in the Capacity of Astrocytes and Microglial Cells of the Offspring to React in Inflammation.

Hypothyroxinemia (Hpx) is a highly frequent condition characterized by low thyroxine (T4) and normal 3,3',5'-triiodothyronine (T3) and thyroid stimulating hormone (TSH) levels in the blood. Gestational Hpx is closely related to cognitive impairment in the human offspring. In animal models gestational Hpx causes impairment at glutamatergic synapsis, spatial learning, and the susceptibility to suffer strong autoimmune diseases like experimental autoimmune encephalomyelitis (EAE). However, the mechanisms underlying these phenotypes are unknown. On the other hand, it has been shown that astrocytes and microglia affect the outcome of EAE. In fact, the activation of astrocytes and microglia in the central nervous system (CNS) contributes to EAE progression. Thus, in this work, the reactivity of astrocytes and microglia from rats gestated in Hpx was evaluated aiming to understand whether these cells are targets of gestational Hpx. Interestingly, microglia derived from the offspring gestated in Hpx were less reactive compared to microglia derived from offspring gestated in euthyroidism. Instead, astrocytes derived from the offspring gestated in Hpx were significantly more reactive than the astrocytes from the offspring gestated in euthyroidism. This work contributes with novel information regarding the effects of gestational Hpx over astrocytes and microglia in the offspring. It suggests that astrocyte could react strongly to an inflammatory insult inducing neuronal death in the CNS.

Ovulation, a sign of health.

The concept of the ovarian continuum can be understood as a process that occurs during a woman's lifetime and begins during intrauterine life with fertilization. Women start their reproductive years with approximately five hundred thousand follicles containing oocytes, of which only around five hundred will be released during ovulation. Ovulation has been recognized as an event linked with reproduction; however, recent evidence supports the role of ovulation as a sign of health. The use of biomarkers that help women recognize ovulation enables them to identify their health status. This knowledge helps medical healthcare providers in the prevention, diagnosis, and treatment of different pathologies related with endocrine disorders, gynecological abnormalities, autoimmune, genetic, and neoplastic diseases, as well as pregnancy-related issues. The knowledge of the ovarian continuum and the use of biomarkers to recognize ovulation should be considered a powerful tool for women and medical professionals. SUMMARY: The ovarian continuum is a process that occurs during a woman's lifetime. It begins during intrauterine life with fertilization and ends with menopause. This process can be greatly affected by different conditions such as changes in hormonal levels and illnesses. Therefore, understanding and promoting the knowledge and use of biomarkers of ovulation in women is a key aspect to consider when evaluating their health status. The knowledge and education about the ovarian continuum should be taken into account as a powerful tool for women and medical professionals.

Glial Cells and Integrity of the Nervous System.

Today, there is enormous progress in understanding the function of glial cells, including astroglia, oligodendroglia, Schwann cells, and microglia. Around 150 years ago, glia were viewed as a glue among neurons. During the course of the twentieth century, microglia were discovered and neuroscientists' views evolved toward considering glia only as auxiliary cells of neurons. However, over the last two to three decades, glial cells' importance has been reconsidered because of the evidence on their involvement in defining central nervous system architecture, brain metabolism, the survival of neurons, development and modulation of synaptic transmission, propagation of nerve impulses, and many other physiological functions. Furthermore, increasing evidence shows that glia are involved in the mechanisms of a broad spectrum of pathologies of the nervous system, including some psychiatric diseases, epilepsy, and neurodegenerative diseases to mention a few. It appears safe to say that no neurological disease can be understood without considering neuron-glia crosstalk. Thus, this book aims to show different roles played by glia in the healthy and diseased nervous system, highlighting some of their properties while considering that the various glial cell types are essential components not only for cell function and integration among neurons, but also for the emergence of important brain homeostasis.

Age-dependent changes on TGFß1 Smad3 pathway modify the pattern of microglial cell activation.

Aging is the main risk factor for Alzheimer's disease. Among other characteristics, it shows changes in inflammatory signaling that could affect the regulation of glial cell activation. We have shown that astrocytes prevent microglial cell cytotoxicity by mechanisms mediated by TGFß1. However, whereas TGFß1 is increased, glial cell activation persists in aging. To understand this apparent contradiction, we studied TGFß1-Smad3 signaling during aging and their effect on microglial cell function. TGFß1 induction and activation of Smad3 signaling in the hippocampus by inflammatory stimulation was greatly reduced in adult mice. We evaluated the effect of TGFß1-Smad3 pathway on the regulation of nitric oxide (NO) and reactive oxygen species (ROS) secretion, and phagocytosis of microglia from mice at different ages with and without in vivo treatment with lipopolysaccharide (LPS) to induce an inflammatory status. NO secretion was only induced on microglia from young mice exposed to LPS, and was potentiated by inflammatory preconditioning, whereas in adult mice the induction of ROS was predominant. TGFß1 modulated induction of NO and ROS production in young and adult microglia, respectively. Modulation was partially dependent on Smad3 pathway and was impaired by inflammatory preconditioning. Phagocytosis was induced by inflammation and TGFß1 only in microglia cultures from young mice. Induction by TGFß1 was also prevented by Smad3 inhibition. Our findings suggest that activation of the TGFß1-Smad3 pathway is impaired in aging. Age-related impairment of TGFß1-Smad3 can reduce protective activation while facilitating cytotoxic activation of microglia, potentiating microglia-mediated neurodegeneration.

Transforming growth factor ß1 modulates amyloid ß-induced glial activation through the Smad3-dependent induction of MAPK phosphatase-1.

Chronic neuroinflammation has been proposed as a driving force for Alzheimer's disease (AD), which is characterized by amyloid-ß (Aß) deposition, neurofibrillary tangles, neuronal loss, and activation of glial cells. Persistent activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) pathway has been reported, which induces an increased expression of inflammatory mediators. Transforming growth factor ß1 (TGFß1) is an inflammation modulator whose levels are increased in AD. However, its canonical signaling pathway, Smad, appears to be impaired. Our previous findings indicate that TGFß1 plays a key role in the pathogenesis of neuroinflammation, but the molecular mechanisms underlying its effects are not completely elucidated. Here, we studied the potential role of MKP-1, a phosphatase that exerts negative regulation on MAPK signaling, in the modulatory actions of TGFß1. Using rat primary glial cultures, we found that pretreatment with TGFß1 for 48 h reduced the production of inflammatory mediators induced by Aß42, a result that was associated with prevention of MAPK p38 activation, attenuation of NF-κB p65 nuclear translocation, and an increase in MKP-1 levels. Moreover, suppression of MKP-1 expression by siRNA and inhibition of Smad3 reversed the modulation of inflammatory response exerted by TGFß1. These results indicate that TGFß1 induces the expression of MKP-1 in glial cells through the Smad pathway and inhibits MAPK and NF-κB signaling, thus revealing a novel mechanism for the neuroprotective actions of TGFß1. Further research would be important in order to characterize the role of this mechanism in the pathogenesis of AD.

Modulation of interferon-γ-induced glial cell activation by transforming growth factor ß1: a role for STAT1 and MAPK pathways.

Overactivated glial cells can produce neurotoxic oxidant molecules such as nitric oxide (NO·) and superoxide anion (O(2)·(-)). We have previously reported that transforming growth factor ß1 (TGFß1) released by hippocampal cells modulates interferon-γ (IFNγ)-induced production of O(2)·(-) and NO· by glial cells. However, underlying molecular mechanisms are not completely understood, thereby, the aim of this work was to study the effect of TGFß1 on IFNγ-induced signaling pathways. We found that costimulation with TGFß1 decreased IFNγ-induced phosphorylation of signal transducer and activator of transcription-type-1 (STAT1) and extracellular signal-regulated kinase (ERK), which correlated with a reduced O(2)·(-) and NO· production in mixed and purified glial cultures. Moreover, IFNγ caused a decrease in TGFß1-mediated phosphorylation of P38, whereas pre-treatment with ERK and P38 inhibitors decreased IFNγ-induced phosphorylation of STAT1 on serine727 and production of radical species. These results suggested that modulation of glial activation by TGFß1 is mediated by deactivation of MAPKs. Notably, TGFß1 increased the levels of MAPK phosphatase-1 (MKP-1), whose participation in TGFß1-mediated modulation was confirmed by MKP-1 siRNA transfection in mixed and purified glial cultures. Our results indicate that the cross-talk between IFNγ and TGFß1 might regulate the activation of glial cells and that TGFß1 modulated IFNγ-induced production of neurotoxic oxidant molecules through STAT1, ERK, and P38 pathways.