Interferon- γ and infectious diseases: Lessons and prospects

Science, Journal Year: 2024, Volume and Issue: 384(6693)

Published: April 18, 2024

Infectious diseases continue to claim many lives. Prevention of morbidity and mortality from these would benefit not just new medicines vaccines but also a better understanding what constitutes protective immunity. Among the major immune signals that mobilize host defense against infection is interferon-γ (IFN-γ), protein secreted by lymphocytes. Forty years ago, IFN-γ was identified as macrophage-activating factor, and, in recent years, there has been resurgent interest biology its role human defense. Here we assess current IFN-γ, revisit designation an "interferon," weigh prospects therapeutic globally pervasive microbial pathogens.

Language: Английский

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An inducible genetic tool to track and manipulate specific microglial states reveals their plasticity and roles in remyelination

Immunity, Journal Year: 2024, Volume and Issue: 57(6), P. 1394 - 1412.e8

Published: May 30, 2024

Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative-region-associated microglia (PAMs) developing white matter disease-associated (DAMs) prevalent various neurodegenerative conditions. PAMs DAMs share a similar core gene signature. However, the extent of dynamism plasticity these states, as well their functional significance, remains elusive, partly due to lack specific tools. Here, we generated an inducible Cre driver line, Clec7a-CreER

Language: Английский

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The immunological perspective of major depressive disorder: unveiling the interactions between central and peripheral immune mechanisms

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Jan. 19, 2025

Major depressive disorder is a prevalent mental disorder, yet its pathogenesis remains poorly understood. Accumulating evidence implicates dysregulated immune mechanisms as key contributors to disorders. This review elucidates the complex interplay between peripheral and central components underlying pathology. Peripherally, systemic inflammation, gut dysregulation, dysfunction in organs including gut, liver, spleen adipose tissue influence brain function through neural molecular pathways. Within nervous system, aberrant microglial astrocytes activation, cytokine imbalances, compromised blood-brain barrier integrity propagate neuroinflammation, disrupting neurotransmission, impairing neuroplasticity, promoting neuronal injury. The crosstalk immunity creates vicious cycle exacerbating neuropathology. Unraveling these multifaceted immune-mediated provides insights into major disorder's pathogenic basis potential biomarkers targets. Modulating both responses represent promising multidimensional therapeutic strategy.

Language: Английский

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Blood–Brain Barrier Breakdown in Neuroinflammation: Current In Vitro Models

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(16), P. 12699 - 12699

Published: Aug. 11, 2023

The blood-brain barrier, which is formed by tightly interconnected microvascular endothelial cells, separates the brain from peripheral circulation. Together with other central nervous system-resident cell types, including pericytes and astrocytes, barrier forms neurovascular unit. Upon neuroinflammation, this becomes leaky, allowing molecules cells to enter potentially harm tissue of system. Despite significance animal models in research, they may not always adequately reflect human pathophysiology. Therefore, are needed. This review will provide an overview terms both health disease. It describe all key elements vitro explore how different compositions can be utilized effectively model a variety neuroinflammatory conditions. Furthermore, it existing types that used basic research study respective pathologies thus far.

Language: Английский

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Microglia: Activity‐dependent regulators of neural circuits

Annals of the New York Academy of Sciences, Journal Year: 2024, Volume and Issue: 1533(1), P. 38 - 50

Published: Jan. 31, 2024

Abstract It has been more than a century since Pío del Río‐Hortega first characterized microglia in histological stains of brain tissue. Since then, significant advances have made understanding the role these resident central nervous system (CNS) macrophages. In particular, it is now known that can sense neural activity and modulate neuronal circuits accordingly. We review mechanisms by which detect changes to then synapse numbers developing mature CNS. This includes responses both spontaneous experience‐driven activity. further discuss activity‐dependent regulate synaptic function circuit excitability. Together, our discussion provides comprehensive functions within healthy CNS, highlights exciting new open questions related fully as key components regulators circuits.

Language: Английский

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Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior

Science, Journal Year: 2024, Volume and Issue: 386(6721)

Published: Oct. 31, 2024

The innate immune system shapes brain development and is implicated in neurodevelopmental diseases. It critical to define the relevant cells signals their impact on circuits. In this work, we found that group 2 lymphoid (ILC2s) cytokine interleukin-13 (IL-13) signaled directly inhibitory interneurons increase synapse density developing mouse brain. ILC2s expanded produced IL-13 meninges. Loss of or signaling decreased inhibitory, but not excitatory, cortical synapses. Conversely, were sufficient pathway led selective impairments social interaction. These data a type neuroimmune circuit early life behavior.

Language: Английский

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Bacterial peptidoglycan signalling in microglia: Activation by MDP via the NF-κB/MAPK pathway

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 121, P. 43 - 55

Published: July 5, 2024

Bacterial peptidoglycan (PGN) fragments are commonly studied in the context of bacterial infections. However, PGN recently gained recognition as signalling molecules from commensal gut microbiota healthy host. Here we focus on minimal bioactive motif muramyl dipeptide (MDP), found both Gram-positive and Gram-negative bacteria, which signals through Nod2 receptor. MDP translocates to brain is associated with changes neurodevelopment behaviour, yet there limited knowledge about underlying mechanisms. In this study demonstrate that physiologically relevant doses induce rapid microglial gene expression lead cytokine chemokine secretion. immortalised (IMG) cells, C-C Motif Chemokine Ligand 5 (CCL5/RANTES) acutely sensitive lowest prevalent dose (0.1 µg/ml) MDP. As CCL5 plays an important role memory formation synaptic plasticity, might be missing link elucidating MDP-induced alterations expression. We observed a higher physiological elevates cytokines TNF-α IL-1β, indicating transition toward pro-inflammatory phenotype IMG was validated primary cultures. Furthermore, induces translocation NF-κB subunit p65 into nucleus, blocked by MAPK p38 inhibitor SB202190, suggesting interplay pathways responsible for MDP-specific phenotype. These findings underscore significance different levels shaping function CNS indicate potential mediator early inflammatory processes brain. It also positions microglia target microbiota-brain-axis pathway signalling.

Language: Английский

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Targeting Cytokine-Mediated Inflammation in Brain Disorders: Developing New Treatment Strategies

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(1), P. 104 - 104

Published: Jan. 15, 2025

Cytokine-mediated inflammation is increasingly recognized for playing a vital role in the pathophysiology of wide range brain disorders, including neurodegenerative, psychiatric, and neurodevelopmental problems. Pro-inflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) cause neuroinflammation, alter function, accelerate disease development. Despite progress understanding these pathways, effective medicines targeting are still limited. Traditional anti-inflammatory immunomodulatory drugs peripheral inflammatory illnesses. Still, they face substantial hurdles when applied to central nervous system (CNS), blood-brain barrier (BBB) unwanted systemic effects. This review highlights developing treatment techniques modifying cytokine-driven focusing on advances that selectively target critical involved pathology. Novel approaches, cytokine-specific inhibitors, antibody-based therapeutics, gene- RNA-based interventions, sophisticated drug delivery systems like nanoparticles, show promise with respect lowering neuroinflammation greater specificity safety. Furthermore, developments biomarker discoveries neuroimaging improving our ability monitor responses, allowing more accurate personalized regimens. Preclinical clinical trial data demonstrate therapeutic potential tailored techniques. However, significant challenges remain, across BBB reducing off-target As research advances, creation personalized, cytokine-centered therapeutics has therapy landscape illnesses, giving patients hope better results higher quality life.

Language: Английский

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Neuroregulation during Bone Formation and Regeneration: Mechanisms and Strategies

ACS Applied Materials & Interfaces, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

The skeleton is highly innervated by numerous nerve fibers. These fibers, in addition to transmitting information within the bone and mediating sensations, play a crucial role regulating tissue formation regeneration. Traditional engineering (BTE) often fails achieve satisfactory outcomes when dealing with large-scale defects, which frequently related lack of effective reconstruction neurovascular network. In recent years, increasing research has revealed critical nerves metabolism. Nerve fibers regulate cells through neurotransmitters, neuropeptides, peripheral glial cells. Furthermore, also coordinate vascular immune systems jointly construct microenvironment favorable for As signaling driver formation, neuroregulation spans entire process physiological activities from embryonic postmaturity remodeling repair. However, there currently comprehensive summaries these regulatory mechanisms. Therefore, this review sketches out function during Then, we elaborate on mechanisms coupling neuromodulation immunity. Finally, discuss several novel strategies neuro-bone (NBTE) based bone, focusing coordinated regeneration tissue.

Language: Английский

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Neuroimmune regulation of the prefrontal cortex tetrapartite synapse

Neuropharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 110335 - 110335

Published: Feb. 1, 2025

The prefrontal cortex (PFC) is an essential driver of cognitive, affective, and motivational behavior. There clear evidence that the neuroimmune system directly influences PFC synapses, in addition to its role as first line defense against toxins pathogens. In this review, we describe core structures form tetrapartite synapse, focusing on signaling microdomain created by astrocytic cradling synapse well emerging extracellular matrix synaptic organization plasticity. Neuroimmune signals (e.g. pro-inflammatory interleukin 1β) can impact function each structure within promote intra-synaptic crosstalk, will provide overview recent advances field. Finally, from post mortem human brain tissue preclinical studies indicate inflammation may be a key contributor dysfunction. Therefore, conclude with mechanistic discussion neuroimmune-mediated maladaptive plasticity neuropsychiatric disorders, focus alcohol use disorder (AUD). Growing recognition system's critical regulator provides strong support for targeting develop new pharmacotherapeutics.

Language: Английский

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