Role of macrophages in HIV pathogenesis and cure: NIH perspectives.

Macrophages play a significant role in HIV infection and contribute to pathogenesis of comorbidities as well as establishment of the viral reservoir in people living with HIV. While CD4+ T cells are considered the main targets of HIV infection, infected macrophages resist the cytopathic effects of infection, contributing to the persistent HIV reservoir. Furthermore, activated macrophages drive inflammation and contribute to the development of comorbidities, including HIV-associated CNS dysfunction. Better understanding the role of macrophages in HIV infection, persistence, and comorbidities can lead to development of innovative therapeutic strategies to address HIV-related outcomes in people living with HIV. In October 2021, the National Institute of Mental Health and the Ragon Institute of MGH, MIT, and Harvard conducted a virtual meeting on role of macrophages in HIV infection, pathogenesis, and cure. This review article captures the key highlights from this meeting and provides an overview of interests and activities of various NIH institutes involved in supporting research on macrophages and HIV.

Metabolic Regulation of Inflammation and Its Resolution: Current Status, Clinical Needs, Challenges, and Opportunities.

Metabolism and inflammation have been viewed as two separate processes with distinct but critical functions for our survival: metabolism regulates the utilization of nutrients, and inflammation is responsible for defense and repair. Both respond to an organism's stressors to restore homeostasis. The interplay between metabolic status and immune response (immunometabolism) plays an important role in maintaining health or promoting disease development. Understanding these interactions is critical in developing tools for facilitating novel preventative and therapeutic approaches for diseases, including cancer. This trans-National Institutes of Health workshop brought together basic scientists, technology developers, and clinicians to discuss state-of-the-art, innovative approaches, challenges, and opportunities to understand and harness immunometabolism in modulating inflammation and its resolution.

Imaging inflammation and its resolution in health and disease: current status, clinical needs, challenges, and opportunities.

Inflammation is a normal process in our body; acute inflammation acts to suppress infections and support wound healing. Chronic inflammation likely leads to a wide range of diseases, including cancer. Tools to locate and monitor inflammation are critical for developing effective interventions to arrest inflammation and promote its resolution. To identify current clinical needs, challenges, and opportunities in advancing imaging-based evaluations of inflammatory status in patients, the U.S. National Institutes of Health convened a workshop on imaging inflammation and its resolution in health and disease. Clinical speakers described their needs for image-based capabilities that could help determine the extent of inflammatory conditions in patients to guide treatment planning and undertake necessary interventions. The imaging speakers showcased the state-of-the-art in vivo imaging techniques for detecting inflammation in different disease areas. Many imaging capabilities developed for 1 organ or disease can be adapted for other diseases and organs, whereas some have promise for clinical utility within the next 5-10 yr. Several speakers demonstrated that multimodal imaging measurements integrated with serum-based measures could improve in robustness for clinical utility. All speakers agreed that multiple inflammatory measures should be acquired longitudinally to comprehend the dynamics of unresolved inflammation that leads to disease development. They also agreed that the best strategies for accelerating clinical translation of imaging inflammation capabilities are through integration between new imaging techniques and biofluid-based biomarkers of inflammation as well as already established imaging measurements.-Liu, C. H., Abrams, N. D., Carrick, D. M., Chander, P., Dwyer, J., Hamlet, M. R. J., Kindzelski, A. L., PrabhuDas, M., Tsai, S.-Y. A., Vedamony, M. M., Wang, C., Tandon, P. Imaging inflammation and its resolution in health and disease: current status, clinical needs, challenges, and opportunities.

Regulation of sigma-1 receptors and endoplasmic reticulum chaperones in the brain of methamphetamine self-administering rats.

sigma-1 Receptors are endoplasmic reticulum (ER) chaperones that are implicated in the neuroplasticity associated with psychostimulant abuse. We immunocytochemically examined the distribution of sigma-1 receptors in the brain of drug-naive rats and then examined the dynamics of sigma-1 receptors and other ER chaperones in specific brain subregions of rats that self-administered methamphetamine, received methamphetamine passively, or received only saline injections. sigma-1 Receptors were found to be expressed in moderate to high levels in the olfactory bulb, striatum, nucleus accumbens shell, olfactory tubercle, amygdala, hippocampus, red nucleus, ventral tegmental area, substantia nigra, and locus ceruleus. Methamphetamine, whether self-administered or passively received, significantly elevated ER chaperones including the sigma-1 receptor, BiP, and calreticulin in the ventral tegmental area and substantia nigra. In the olfactory bulb, however, only the sigma-1 receptor chaperone was increased, and this increase occurred only in rats that actively self-administered methamphetamine. Consistent with an increase in sigma-1 receptors, extracellular signal-regulated kinase was found to be activated and protein kinase A attenuated in the olfactory bulb of methamphetamine self-administering rats. sigma-1 Receptors in the olfactory bulb were found to be colocalized with dopamine D1 receptors. These results indicate that methamphetamine induces ER stress in the ventral tegmental area and substantia nigra in rats whether the drug is received actively or passively. However, the changes seen only in rats that actively self-administered methamphetamine suggest that D1 and sigma-1 receptors in the olfactory bulb might play an important role in the motivational conditioning/learning aspects of methamphetamine self-administration in the rat.

Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1xGTP pathway.

Sigma-1 receptors (Sig-1Rs) are endoplasmic reticulum (ER)-resident proteins known to be involved in learning and memory. Dendritic spines in hippocampal neurons play important roles in neuroplasticity and learning and memory. This study tested the hypothesis that Sig-1Rs might regulate denritic spine formation in hippocampal neurons and examined potential mechanisms therein. In rat hippocampal primary neurons, the knockdown of Sig-1Rs by siRNAs causes a deficit in the formation of dendritic spines that is unrelated to ER Ca(2+) signaling or apoptosis, but correlates with the mitochondrial permeability transition and cytochrome c release, followed by caspase-3 activation, Tiam1 cleavage, and a reduction in Rac1.GTP. Sig-1R-knockdown neurons contain higher levels of free radicals when compared to control neurons. The activation of superoxide dismutase or the application of the hydroxyl-free radical scavenger N-acetyl cysteine (NAC) to the Sig-1R-knockdown neurons rescues dendritic spines and mitochondria from the deficits caused by Sig-1R siRNA. Further, the caspase-3-resistant TIAM1 construct C1199DN, a stable guanine exchange factor able to constitutively activate Rac1 in the form of Rac1.GTP, also reverses the siRNA-induced dendritic spine deficits. In addition, constitutively active Rac1.GTP reverses this deficit. These results implicate Sig-1Rs as endogenous regulators of hippopcampal dendritic spine formation and suggest a free radical-sensitive ER-mitochondrion-Rac1.GTP pathway in the regulation of dendritic spine formation in the hippocampus.

Sigma-1 receptor chaperones and diseases.

Chaperones are proteins that assist the correct folding of other protein clients either when the clients are being synthesized or at their functional localities. Chaperones are responsible for certain diseases. The sigma-1 receptor is recently identified as a receptor chaperone whose activity can be activated/deactivated by specific ligands. Under physiological conditions, the sigma-1 receptor chaperones the functional IP3 receptor at the endoplasmic reticulum and mitochondrion interface to ensure proper Ca(2+) signaling from endoplasmic reticulum into mitochondrion. However, under pathological conditions whereby cells encounter enormous stress that results in the endoplasmic reticulum losing its global Ca(2+) homeostasis, the sigma-1 receptor translocates and counteracts the arising apoptosis. Thus, the sigma-1 receptor is a receptor chaperone essential for the metabotropic receptor signaling and for the survival against cellular stress. The sigma-1 receptor has been implicated in many diseases including addiction, pain, depression, stroke, and cancer. Whether the chaperone activity of the sigma-1 receptor attributes to those diseases awaits further investigation.

A mechanism for the inhibition of neural progenitor cell proliferation by cocaine.

BACKGROUND: Prenatal exposure of the developing brain to cocaine causes morphological and behavioral abnormalities. Recent studies indicate that cocaine-induced proliferation inhibition and/or apoptosis in neural progenitor cells may play a pivotal role in causing these abnormalities. To understand the molecular mechanism through which cocaine inhibits cell proliferation in neural progenitors, we sought to identify the molecules that are responsible for mediating the effect of cocaine on cell cycle regulation. METHODS AND FINDINGS: Microarray analysis followed by quantitative real-time reverse transcription PCR was used to screen cocaine-responsive and cell cycle-related genes in a neural progenitor cell line where cocaine exposure caused a robust anti-proliferative effect by interfering with the G1-to-S transition. Cyclin A2, among genes related to the G1-to-S cell cycle transition, was most strongly down-regulated by cocaine. Down-regulation of cyclin A was also found in cocaine-treated human primary neural and A2B5+ progenitor cells, as well as in rat fetal brains exposed to cocaine in utero. Reversing cyclin A down-regulation by gene transfer counteracted the proliferation inhibition caused by cocaine. Further, we found that cocaine-induced accumulation of reactive oxygen species, which involves N-oxidation of cocaine via cytochrome P450, promotes cyclin A down-regulation by causing an endoplasmic reticulum (ER) stress response, as indicated by increased phosphorylation of eIF2alpha and expression of ATF4. In the developing rat brain, the P450 inhibitor cimetidine counteracted cocaine-induced inhibition of neural progenitor cell proliferation as well as down-regulation of cyclin A. CONCLUSIONS: Our results demonstrate that down-regulation of cyclin A underlies cocaine-induced proliferation inhibition in neural progenitors. The down-regulation of cyclin A is initiated by N-oxidative metabolism of cocaine and consequent ER stress. Inhibition of cocaine N-oxidative metabolism by P450 inhibitors may provide a preventive strategy for counteracting the adverse effects of cocaine on fetal brain development.

Picomolar concentrations of hibernation induction delta opioid peptide [D-Ala2,D-Leu5]enkephalin increase the nerve growth factor in NG-108 cells.

The delta opioid peptide [D-Ala2,D-Leu5]enkephalin (DADLE) has been shown to be a neuroprotective agent via mechanisms that are not totally understood. We previously demonstrated that the i.p. injection of DADLE in mice causes an increase of nerve growth factor (NGF) in the brain. To further clarify the NGF-increasing action of DADLE, we examined here the NGF-increasing effect of DADLE in vitro, using cultured NG-108 cells. DADLE dose-dependently increases the immunoreactive level of NGF in NG-108 cells in a bell-shape manner, with the effective DADLE concentrations in the picomolar range (0.01-100 pM). Also, DADLE at 1 pM selectively increases c-Jun and c-Fos, but not c-Rel. These results indicate that DADLE is one of the most potent agents in increasing the NGF in the biological system and that this action of DADLE involves selective increases of c-Jun and c-Fos, transcription factors that promote the NGF expression.