Living bioelectronics resolve inflammation Olofsson, Peder S
Science (American Association for the Advancement of Science),
2024-May-31, 2024-05-31, 20240531, Volume:
384, Issue:
6699
Journal Article
Peer reviewed
Coupling skin bacteria and electronics opens paths to adaptive treatment of inflammation.
Neural reflex circuits regulate cytokine release to prevent potentially damaging inflammation and maintain homeostasis. In the inflammatory reflex, sensory input elicited by infection or injury ...travels through the afferent vagus nerve to integrative regions in the brainstem, and efferent nerves carry outbound signals that terminate in the spleen and other tissues. Neurotransmitters from peripheral autonomic nerves subsequently promote acetylcholine‐release from a subset of CD4+ T cells that relay the neural signal to other immune cells, e.g. through activation of α7 nicotinic acetylcholine receptors on macrophages. Here, we review recent progress in the understanding of the inflammatory reflex and discuss potential therapeutic implications of current findings in this evolving field.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The inflammasome regulates the release of caspase activation-dependent cytokines, including interleukin (IL)-1β, IL-18 and high-mobility group box 1 (HMGB1). By studying HMGB1 release mechanisms, ...here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacological inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminium, rotenone, live Escherichia coli, anthrax lethal toxin, DNA transfection and Salmonella typhimurium infection. PKR deficiency significantly inhibited the secretion of IL-1β, IL-18 and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell-free system with recombinant NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC, also known as PYCARD) and pro-caspase-1 reconstitutes inflammasome activity. These results show a crucial role for PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation.
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IJS, KISLJ, NUK, UL, UM, UPUK
Appropriate control of immune responses is a critical determinant of health. Here, we show that choline acetyltransferase (ChAT) is expressed and ACh is produced by B cells and other immune cells ...that have an impact on innate immunity. ChAT expression occurs in mucosal-associated lymph tissue, subsequent to microbial colonization, and is reduced by antibiotic treatment. MyD88-dependent Toll-like receptor up-regulates ChAT in a transient manner. Unlike the previously described CD4 ⁺ T-cell population that is stimulated by norepinephrine to release ACh, ChAT ⁺ B cells release ACh after stimulation with sulfated cholecystokinin but not norepinephrine. ACh-producing B-cells reduce peritoneal neutrophil recruitment during sterile endotoxemia independent of the vagus nerve, without affecting innate immune cell activation. Endothelial cells treated with ACh in vitro reduced endothelial cell adhesion molecule expression in a muscarinic receptor-dependent manner. Despite this ability, ChAT ⁺ B cells were unable to suppress effector T-cell function in vivo. Therefore, ACh produced by lymphocytes has specific functions, with ChAT ⁺ B cells controlling the local recruitment of neutrophils.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The mammalian immune system and the nervous system coevolved under the influence of cellular and environmental stress. Cellular stress is associated with changes in immunity and activation of the ...NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, a key component of innate immunity. Here we show that α7 nicotinic acetylcholine receptor (α7 nAchR)-signaling inhibits inflammasome activation and prevents release of mitochondrial DNA, an NLRP3 ligand. Cholinergic receptor agonists or vagus nerve stimulation significantly inhibits inflammasome activation, whereas genetic deletion of α7 nAchR significantly enhances inflammasome activation. Acetylcholine accumulates in macrophage cytoplasm after adenosine triphosphate (ATP) stimulation in an α7 nAchR-independent manner. Acetylcholine significantly attenuated calcium or hydrogen oxide-induced mitochondrial damage and mitochondrial DNA release. Together, these findings reveal a novel neurotransmitter-mediated signaling pathway: acetylcholine translocates into the cytoplasm of immune cells during inflammation and inhibits NLRP3 inflammasome activation by preventing mitochondrial DNA release.
Atherosclerotic plaques develop in the inner intimal layer of arteries and can cause heart attacks and strokes
. As plaques lack innervation, the effects of neuronal control on atherosclerosis remain ...unclear. However, the immune system responds to plaques by forming leukocyte infiltrates in the outer connective tissue coat of arteries (the adventitia)
. Here, because the peripheral nervous system uses the adventitia as its principal conduit to reach distant targets
, we postulated that the peripheral nervous system may directly interact with diseased arteries. Unexpectedly, widespread neuroimmune cardiovascular interfaces (NICIs) arose in mouse and human atherosclerosis-diseased adventitia segments showed expanded axon networks, including growth cones at axon endings near immune cells and media smooth muscle cells. Mouse NICIs established a structural artery-brain circuit (ABC): abdominal adventitia nociceptive afferents
entered the central nervous system through spinal cord T
-T
dorsal root ganglia and were traced to higher brain regions, including the parabrachial and central amygdala neurons; and sympathetic efferent neurons projected from medullary and hypothalamic neurons to the adventitia through spinal intermediolateral neurons and both coeliac and sympathetic chain ganglia. Moreover, ABC peripheral nervous system components were activated: splenic sympathetic and coeliac vagus nerve activities increased in parallel to disease progression, whereas coeliac ganglionectomy led to the disintegration of adventitial NICIs, reduced disease progression and enhanced plaque stability. Thus, the peripheral nervous system uses NICIs to assemble a structural ABC, and therapeutic intervention in the ABC attenuates atherosclerosis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
The hallmark of inflammatory bowel diseases (IBD) is chronic intestinal inflammation with typical onset in adolescents and young adults. An abundance of neutrophils is seen in the ...inflammatory lesions, but adaptive immunity is also an important player in the chronicity of the disease. There is an unmet need for new treatment options since modern medicines such as biological therapy with anti-cytokine antibodies still leave a substantial number of patients with persisting disease activity. The role of the central nervous system and its interaction with the gut in the pathophysiology of IBD have been brought to attention both in animal models and in humans after the discovery of the inflammatory reflex. The suggested control of gut immunity by the brain–gut axis represents a novel therapeutic target suitable for bioelectronic intervention. In this review, we discuss the role of the inflammatory reflex in gut inflammation and the recent advances in the treatment of IBD by intervening with the brain–gut axis through bioelectronic devices.
Bioelectronic medicine.
Neural circuits regulate cytokine production to prevent potentially damaging inflammation. A prototypical vagus nerve circuit, the inflammatory reflex, inhibits tumor necrosis factor—α production in ...spleen by a mechanism requiring acetylcholine signaling through the α7 nicotinic acetylcholine receptor expressed on cytokine-producing macrophages. Nerve fibers in spleen lack the enzymatic machinery necessary for acetylcholine production; therefore, how does this neural circuit terminate in cholinergic signaling? We identified an acetylcholine-producing, memory phenotype T cell population in mice that is integral to the inflammatory reflex. These acetylcholine-producing T cells are required for inhibition of cytokine production by vagus nerve stimulation. Thus, action potentials originating in the vagus nerve regulate T cells, which in turn produce the neurotransmitter, acetylcholine, required to control innate immune responses.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Biointegrated neuromorphic hardware holds promise for new protocols to record/regulate signalling in biological systems. Making such artificial neural circuits successful requires minimal ...device/circuit complexity and ion-based operating mechanisms akin to those found in biology. Artificial spiking neurons, based on silicon-based complementary metal-oxide semiconductors or negative differential resistance device circuits, can emulate several neural features but are complicated to fabricate, not biocompatible and lack ion-/chemical-based modulation features. Here we report a biorealistic conductance-based organic electrochemical neuron (c-OECN) using a mixed ion-electron conducting ladder-type polymer with stable ion-tunable antiambipolarity. The latter is used to emulate the activation/inactivation of sodium channels and delayed activation of potassium channels of biological neurons. These c-OECNs can spike at bioplausible frequencies nearing 100 Hz, emulate most critical biological neural features, demonstrate stochastic spiking and enable neurotransmitter-/amino acid-/ion-based spiking modulation, which is then used to stimulate biological nerves in vivo. These combined features are impossible to achieve using previous technologies.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Cognitive impairment and psychological distress are common in intensive care unit (ICU) survivors. Early identification of affected individuals is important, so intervention and treatment can be ...utilized at an early stage. Cognitive Failures Questionnaire (CFQ) is commonly used to screen for subjective cognitive function, but it is unclear whether CFQ scores correlate to objective cognitive function in this population.
Between 2014 and 2018, 100 ICU survivors aged 18-70 years from the general ICU at the Karolinska University Hospital, Solna, were included in the study. Out of these, 58 patients completed follow-up at 3 months after ICU discharge, 51 at 6 months, and 45 at 12 months. Follow-up included objective cognitive function testing using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and subjective cognitive function testing with the self-rating Cognitive Failures Questionnaire (CFQ), as well as psychological self-rating with the Post-Traumatic Stress Symptoms Scale-10 (PTSS-10) and Hospital Anxiety and Depression Scale (HADS).
The prevalence of cognitive impairment as measured by four selected CANTAB tests was 34% at 3 months after discharge, 18% at 6 months, and 16% at 12 months. There was a lack of significant correlation between CANTAB scores and CFQ scores at 3 months (r = - 0.134-0.207, p > 0.05), at 6 months (r = - 0.106-0.257, p > 0.05), and at 12 months after discharge (r = - 0.070-0.109, p > 0.05). Correlations between CFQ and PTSS-10 scores and HADS scores, respectively, were significant over the follow-up period (r = 0.372-0.710, p ≤ 0.001-0.023). In contrast, CANTAB test scores showed a weak correlation with PTSS-10 and HADS scores, respectively, at 3 months only (r = - 0.319-0.348, p = 0.008-0.015).
We found no clinically relevant correlation between subjective and objective cognitive function in this cohort of ICU survivors, while subjective cognitive function correlated significantly with psychological symptoms throughout the follow-up period. Treatment and evaluation of ICU survivors' recovery need to consider both subjective and objective aspects of cognitive impairment, and subjective reports must be interpreted with caution as an indicator of objective cognitive function.
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