Rola makrofagów i monocytów w infekcji SARS-CoV-2 i w ciężkim przebiegu COVID-19

W tej pracy przeglądowej opisuję, w jaki sposób makrofagi biorą udział zarówno w obronie organizmu przed zakażeniem SARS-CoV-2 i COVID-19 i jak mogą przyczyniać się do ciężkiego przebiegu tej choroby. Makrofagi stanowią pierwszą linię obrony organizmu przed wniknięciem wirusów, w tym koronawirusa SARS-CoV-2. Wywołują one m.in. stan zapalny pozwalający na konsolidację działania całego układu odpornościowego w COVID-19. Makrofagi są jednak również zakażane koronawirusem, a wówczas wydzielają zbyt dużo cytokin i tracą zdolność do wygaszania stanu zapalnego. Nikotyna, działając na receptory nikotynowe ACh α4/α7 (nAChR) może łagodzić prozapalne działanie zakażonych SARS-CoV-2 makrofagów i zmniejszać wywołaną przez nie burzę cytokinową w płucach. Monocyty, które są komórkami prekursorowymi makrofagów, i makrofagi tkankowe mogą przenosić SARS-CoV-2 u pacjentów do takich narządów jak: jądra, najądrza czy trzustka i wywoływać w nich proces zapalny, który w przypadku trzustki może powodować cukrzycę.

Neuronal Menin Overexpression Rescues Learning and Memory Phenotype in CA1-Specific α7 nAChRs KD Mice

The perturbation of nicotinic cholinergic receptors is thought to underlie many neurodegenerative and neuropsychiatric disorders, such as Alzheimer’s and schizophrenia. We previously identified that the tumor suppressor gene, MEN1, regulates both the expression and synaptic targeting of α7 nAChRs in the mouse hippocampal neurons in vitro. Here we sought to determine whether the α7 nAChRs gene expression reciprocally regulates the expression of menin, the protein encoded by the MEN1 gene, and if this interplay impacts learning and memory. We demonstrate here that α7 nAChRs knockdown (KD) both in in vitro and in vivo, initially upregulated and then subsequently downregulated menin expression. Exogenous expression of menin using an AAV transduction approach rescued α7 nAChRs KD mediated functional and behavioral deficits specifically in hippocampal (CA1) neurons. These effects involved the modulation of the α7 nAChR subunit expression and functional clustering at the synaptic sites. Our data thus demonstrates a novel and important interplay between the MEN1 gene and the α7 nAChRs in regulating hippocampal-dependent learning and memory.

Tonic engagement of nicotinic receptors bidirectionally controls striatal spiny projection neuron spike timing

Striatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process is fine-tuned by striatal GABAergic interneurons (GINs), which receive overlapping cortical inputs and mediate rapid corticostriatal feedforward inhibition of SPNs. Adding another level of control, cholinergic interneurons (CINs), which are also vigorously activated by corticostriatal excitation, can 1) disynaptically inhibit SPNs by activating α4β2 nicotinic acetylcholine receptors (nAChRs) on various GINs and 2) directly modulate corticostriatal synaptic strength via pre-synaptic α7 nAChR receptors. Measurements of the disynaptic inhibitory pathway, however, indicate that it is too slow to compete with direct GIN-mediated feed-forward inhibition. Moreover, functional nAChRs are also present on populations of GINs that do not respond to phasic activation of CINs, such as parvalbumin-positive fast-spiking interneurons (PV-FSIs), making the overall role of nAChRs in shaping striatal synaptic integration unclear. Using acute striatal slices we show that upon synchronous optogenetic activation of corticostriatal projections, blockade of α7 nAChRs delayed SPN spikes, whereas blockade of α4β2 nAChRs advanced SPN spikes and increased postsynaptic depolarizations. The nAChR-dependent inhibition was mediated by downstream GABA release, and data suggest that the GABA source was not limited to GINs that respond to phasic CIN activation. In particular, the observed spike-advancement caused by nAChR blockade was associated with a diminished frequency of spontaneous inhibitory postsynaptic currents in SPNs, and a parallel hyperpolarization of PV-FSIs. Taken together, we describe opposing roles for tonic (as opposed to phasic) engagement of nAChRs in striatal function. We conclude that tonic activation of nAChRs by CINs both sharpens the temporal fidelity of corticostriatal signaling via pre-synaptic α7 nAChRs and maintains a GABAergic brake on cortically-driven striatal output, processes that may shape SPN spike timing, striatal processing and synaptic plasticity.

Choline Glycerophosphate and Silymarin Modulate Brain and Intestinal Injuries in Rats Exposed to Gamma-Radiation

This work aims to investigate the possible effect of choline glycerophosphate alone or combined with silymarin administration in modulating whole body gamma irradiation-induced brain and intestinal injuries in rats. Rats were irradiated with 7 Gy then subjected to choline glycerophosphate and/ or silymarin for two weeks. At the end of the experiment, the animals were sacrificed and brain and intestine samples were dissected for biochemical, molecular and histopathological examinations. The results showed that choline glycerophosphate, alone or combined with silymarin, ameliorated the adverse effects of radiation as revealed by the inhibition of oxidative stress, apoptotic and inflammatory markers (MDA, Caspase 3, TNF alpha, IL-1β and NF-kB). However, TAC, anti-inflammatory marker, IL-10 and IkBa mRNA were increased. This was also accompanied by a significant increase in the Ach level, ChAT activity and α7 nAChR mRNA expression and a significant decrease in the activity of AChE as compared with the corresponding values of the irradiated group. Moreover, a reduction in the tissue lesions were observed in brain and intestinal tissues. In conclusion, choline glycerophosphate and silymarin exhibited modulating effect against detrimental effects of gamma radiation via cholinergic anti-inflammatory pathway.

Endogenous α7 nAChR Agonist SLURP1 Facilitates Escherichia coli K1 Crossing the Blood-Brain Barrier

Alpha 7 nicotinic acetylcholine receptor (α7 nAChR) is critical for the pathogenesis of Escherichia coli (E. coli) K1 meningitis, a severe central nervous system infection of the neonates. However, little is known about how E. coli K1 manipulates α7 nAChR signaling. Here, through employing immortalized cell lines, animal models, and human transcriptional analysis, we showed that E. coli K1 infection triggers releasing of secreted Ly6/Plaur domain containing 1 (SLURP1), an endogenous α7 nAChR ligand. Exogenous supplement of SLURP1, combined with SLURP1 knockdown or overexpression cell lines, showed that SLURP1 is required for E. coli K1 invasion and neutrophils migrating across the blood-brain barrier (BBB). Furthermore, we found that SLURP1 is required for E. coli K1-induced α7 nAChR activation. Finally, the promoting effects of SLURP1 on the pathogenesis of E. coli K1 meningitis was significantly abolished in the α7 nAChR knockout mice. These results reveal that E. coli K1 exploits SLURP1 to activate α7 nAChR and facilitate its pathogenesis, and blocking SLURP1-α7 nAChR interaction might represent a novel therapeutic strategy for E. coli K1 meningitis.

Neuroinflammation Modulation via a7 Nicotinic Acetylcholine Receptor and Its Chaperone, RIC-3

Nicotinic acetylcholine receptors (nAChRs) are widely expressed in or on various cell types and have diverse functions. In immune cells nAChRs regulate proliferation, differentiation and cytokine release. Specifically, activation of the α7 nAChR reduces inflammation as part of the cholinergic anti-inflammatory pathway. Here we review numerous effects of α7 nAChR activation on immune cell function and differentiation. Further, we also describe evidence implicating this receptor and its chaperone RIC-3 in diseases of the central nervous system and in neuroinflammation, focusing on multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Deregulated neuroinflammation due to dysfunction of α7 nAChR provides one explanation for involvement of this receptor and of RIC-3 in neurodegenerative diseases. In this review, we also provide evidence implicating α7 nAChRs and RIC-3 in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) involving neuroinflammation. Besides, we will describe the therapeutic implications of activating the cholinergic anti-inflammatory pathway for diseases involving neuroinflammation.

A Functional Interaction Between the SARS-CoV-2 Spike Protein and the Human α7 Nicotinic Receptor

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infection relies on the binding of the viral spike protein (S) to angiotensin-converting enzyme 2 in host cells. The S protein has been suggested to interact with nicotinic acetylcholine receptors (nAChRs), and a potential contribution of nAChRs to COVID-19 pathophysiology has been proposed. α7 nAChR is an interesting candidate target since it is present in neuronal and non-neuronal cells, including immune cells, and has anti-inflammatory actions. We here identified a novel direct functional interaction between the α7 nAChR and the Y674-R685 S region. The S fragment exerts a dual effect, acting as a low-efficacy agonist and a non-competitive inhibitor. It activates the α7 nAChR, in line with our previous molecular dynamics simulations showing favorable binding of this accessible region of the S protein to the nAChR agonist binding pocket. However, activation requires the presence of positive allosteric modulators that enhance channel opening probability, indicating very low activation efficacy. The S fragment also induces an overlapped non-competitive inhibition, which may be the predominant effect on α7 responses. This study provides unequivocal evidence supporting a functional α7-S protein interaction, which opens doors for exploring the involvement of nAChRs in COVID-19 pathophysiology.

The utility of PET imaging in the diagnosis and management of psychosis: a brief review

Purpose Advances in the pathophysiological characterization of psychosis has led to a newfound role of biomarkers in diagnostic and prognostic contexts. Further, advances in the accuracy and sensitivity of nuclear medicine imaging techniques, and specifically positron emission tomography (PET), have improved the ability to diagnose and manage individuals experiencing first-episode psychosis or those at greater risk for developing psychosis. Methods Literature searches were performed in PubMed, Google Scholar, and Web of Science to identify papers related to the use of PET imaging in the diagnosis or management of psychosis. Search terms used included “positron emission tomography”, “PET imaging”, “psychosis”, “disorders of psychosis”, “schizophrenia”, “biomarkers”, “diagnostic biomarkers”, “prognostic biomarker”, “monitoring biomarker”, “outcome biomarker”, and “predictive biomarker.” Results Studies included fell into three categories: those examining microglia, those studying dopamine synthesis capacity, and those examining acetylcholine receptor activity. Microglial imaging has been shown to be ineffective in all patients with psychosis, but some believe it shows promise in a subset of patients with psychosis, although no defining characteristics of said subset have been postulated. Studies of dopamine synthesis capacity suggest that presynaptic dopamine is reliably elevated in patients with psychosis, but levels of dopamine active transporter are not. Further, positron emission tomography (PET) with [18F]fluoro-l-dihydroxyphenylalanine ([18F]FDOPA)-PET has been recently used successfully as a predictive biomarker of dopaminergic treatment response, although more work is needed to validate such findings. Finally, existing studies have also documented lower levels of binding to the α7 nicotinic cholinergic receptor (α7-nAChR) via [18F]-ASEM PET in patients with psychosis, however there is a dearth of prospective, randomized studies evaluating the efficacy of [18F]-ASEM as a diagnostic or monitoring biomarker of any kind. Conclusion Molecular imaging has become a useful tool in the diagnosis and management of psychosis. Further work must be done to improve the comparative prognostic value and diagnostic accuracy of different radiotracers.

Sulfonium Ligands of the α7 nAChR

The α7 nicotinic acetylcholine receptor (nAChR) is an important target given its role in cognitive function as well as in the cholinergic anti-inflammatory pathway, where ligands that are effective at stabilizing desensitized states of the receptor are of particular interest. The typical structural element associated with a good desensitizer is the ammonium pharmacophore, but recent work has identified that a trivalent sulfur, in the positively charged sulfonium form, can substitute for the nitrogen in the ammonium pharmacophore. However, the breadth and scope of employing the sulfonium group is largely unexplored. In this work, we have surveyed a disparate group of sulfonium compounds for their functional activity with α7 as well as other nAChR subtypes. Amongst them, we found that there is a wide range of ability to induce α7 desensitization, with 4-hydroxyphenyldimethylsulfonium and suplatast sulfonium salts being the most desensitizing. The smallest sulfonium compound, trimethylsulfonium, was a partial agonist for α7 and other neuronal nAChR. Molecular docking into the α7 receptor extracellular domain revealed preferred poses in the orthosteric binding site for all but one compound, with typical cation–pi interactions as seen with traditional ammonium compounds. A number of the compounds tested may serve as useful platforms for further development of α7 desensitizing ability and for receptor subtype selectivity.