Psychiatric disorders have long been associated with inflammation- either as prolonged mental illnesses leading to immune dysregulations or as psychiatric conditions arising from systemic inflammation. Physiologically, inflammation is one of the responses to bodily stress, however, the degree of inflammation depends on the type and duration of the stressor. Here, we focus on understanding both- inflammation-induced brain cellular response alterations and neuroinflammation caused by an underlying psychiatric condition. Apart from post-mortem brains, the closest approach by which one can recreate both these phenomena are by using patient-derived induced pluripotent stem cells (IPSCs), as the brain tissue is inaccessible. Therefore, we focus on studies using IPSC-derived brain cells from patients to model inflammation across psychiatric conditions. Unlike any other available model system, IPSCs hold a major advantage of carrying patients' genetic background that is crucial to understand disorders as complex and enigmatic as psychiatric disorders. When knowledge on patients' genetic risks and environmental exposures are integrated into patient iPSC-derived brain cellular models, it holds enormous potential to delineate psychiatry related pathophysiology from other comorbidities. Therefore, understanding the cellular responses to inflammation and treatment helps us refine the existing therapeutic strategies and initiate early interventions to better manage psychiatric disorders.
Microglia perform the function of CNS macrophages and act as the primary immune cells in the brain. They surveil the environment, phagocytose cellular debris, maintain homeostasis and respond to tissue damage. While under physiological conditions they play a role in supporting neurons, activated microglia participate directly in the degeneration of neurons in the substantia nigra, as the hallmark of the Parkinsons disease (PD). Their detrimental effects result from direct phagocytosis of dopaminergic neurons as well as via neuroinflammation and release of toxic reactive oxygen and nitrogen species. This pathological shift is driven by a complex interplay of genetic predispositions, such as LRRK2 and GBA mutations, and environmental triggers like toxins and gut dysbiosis.A central mechanism of this neurodegeneration involves extracellular α-synuclein acting as a danger signal (DAMP), which activates microglial Toll-like receptors (e.g., TLR2) to initiate a severe inflammatory cascade. Furthermore, the extreme biophysical stability of aggregated α-synuclein overwhelms the microglial endolysosomal network, leading to lysosomal failure, "frustrated phagocytosis," and the active propagation of the disease via exosomal shedding. Relieving this maladaptive chronic neuroinflammation is a primary therapeutic goal. Modern strategies aim to break this vicious cycle through precise interventions like NLRP3 inflammasome inhibition and autophagy enhancement. Concurrently, advanced fluid biomarkers, such as seed amplification assays (SAA), alongside multidimensional neuroimaging techniques (PET, SPECT, MRI), are proving crucial for detecting these early microglial and pathological changes to guide personalized, disease-modifying therapies of PD.
Parkinson's disease (PD) pathology extends well beyond dopaminergic neuronal loss, with glial cells-microglia and astrocytes-emerging as active architects of α-synuclein spread rather than passive bystanders. This review synthesises current evidence on how mutations in Leucine-Rich Repeat Kinase 2 (LRRK2), the most common genetic cause of familial PD, fundamentally corrupt glial handling of extracellular α-synuclein. We first outline the biology of extracellular α-synuclein-its cellular sources, conformational spectrum, prion-like propagation mechanisms, and principal glial clearance routes-before examining LRRK2 domain architecture, its downstream Rab GTPase signalling cascade, and the cellular processes it governs in glia. We then detail how LRRK2 mutations reconfigure microglial responses: driving constitutive NLRP3 inflammasome priming, impairing phagolysosomal degradation of α-synuclein aggregates, and redirecting phagocytosed cargo into pathogenic exosomal release via the LRRK2-Rab10-LYTL axis. In astrocytes, LRRK2 mutations disrupt annexin A2-mediated phagocytosis, impair chaperone-mediated autophagy and lysosomal acidification, deplete membrane cholesterol through Rab8A/Rab10 hyperphosphorylation, compromise glutamate transporter surface expression, and promote the secretion of phospho-α-synuclein-enriched extracellular vesicles that are neurotoxic to co-cultured dopaminergic neurons. Crucially, dysfunctional microglia and astrocytes do not operate independently-they form a self-amplifying feed-forward circuit in which microglial cytokines (IL-1α, TNF-α, C1q) drive A1 astrocyte conversion, tunnelling nanotube-mediated aggregate exchange propagates rather than resolves α-synuclein burden, and successive waves of neuronal death perpetuate the cycle. We highlight that these mechanisms are mutation-specific: the GTPase-domain variant I1371V, characterised through our group's patient-derived iPSC platform, drives qualitatively distinct membrane and metabolic dysfunction compared with the kinase-domain variant G2019S, underscoring the need for variant-tailored therapeutic strategies. We review human iPSC-based models-including microglia-like cells, midbrain-patterned astrocytes, and 3D midbrain organoids-that have proven indispensable for resolving cell-autonomous from non-cell-autonomous contributions of LRRK2 mutations. Finally, we evaluate emerging therapeutic strategies targeting LRRK2 kinase activity, NLRP3 inflammasome activation, extracellular α-synuclein immunotherapy, and glial lysosomal enhancement, including intranasal mesenchymal stromal cell-derived small extracellular vesicles. We conclude by identifying key unanswered questions regarding the relative dominance of microglial versus astrocytic clearance at different disease stages, the full pathogenic landscape of understudied LRRK2 variants, and the tractability of glial biomarkers as pharmacodynamic endpoints in clinical trials.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra. Other neuropathological hallmarks include α-synuclein aggregation, Lewy bodies, Lewy neurites, and neuroinflammation in the brain. It has been proposed that the α-synuclein pathology starts in the gut with the non-motor symptoms, and then it propagates to the brain via the vagus nerve causing motor symptoms. The immune cells in the brain, namely microglia and astrocytes trigger innate immune responses and the infiltrating T cells are a part of adaptive immune response. The production of cytokines and chemokines enhances neuroinflammation. In the periphery, the monocytes and CD4+ and CD8+ T cells activation increases, causing inflammation. As inflammation is the key pathological hallmark of PD, it has emerged as an attractive target for immunotherapies. The active and passive immunotherapeutic drugs target the α-syn aggregates to overcome neuroinflammation and other motor and non-motor symptoms.
Neuroinflammation shaped by aberrant cellular interactions represents a hallmark of neurodegenerative diseases of the central nervous system (CNS). Microglia are specialized tissue-resident macrophages that reside in the CNS parenchyma and have emerged as central regulators of this aberrant cellular crosstalk. They integrate local signals and orchestrate the cellular interaction networks that underlie disease progression. Recent advances in single-cell and single-nucleus omics, in combination with spatially resolved approaches, have substantially advanced our understanding of microglial dynamics in neurodegeneration. These technological and conceptual advances have revealed an unexpected diversity of disease-associated microglial states and highlighted microglia as central organizers of multicellular interaction networks within diseased CNS tissue. In this chapter, we discuss how these advances have reshaped our understanding of microglia-centered cellular crosstalk in neurodegeneration. We focus on the diversification of neurodegenerative CNS microglial states, the interaction of microglia with neurons, glial cells, adaptive immune cells, and the vasculature. We further discuss how this framework provides a basis for therapeutic strategies aimed at modulating, replacing, or reprogramming microglia in neurodegenerative disease.
Neurodegenerative diseases are increasingly understood as conditions of disrupted neuroimmune homeostasis in which microglia play an important, dynamic, and state-dependent role. Beyond their immune functions, microglia continuously monitor neuronal activity, participate in synaptic remodeling, and contribute to neural circuit regulation in ways that vary across brain regions, disease types, and stages of neurodegeneration. In parallel, neuromodulation can modify neural activity patterns, thereby influencing downstream cellular responses and immune-related signaling within the central nervous system. Accumulating experimental evidence suggests that neuromodulatory interventions can influence microglial state, morphology, and function through activity-dependent neuron-microglia interactions and modulation of inflammatory signaling pathways. By synthesizing findings from both experimental animal models and translational human studies, this chapter presents a mechanistic framework for examining how neuromodulation may be leveraged to modulate microglial activity in neurodegenerative diseases. This approach integrates current understanding of microglial heterogeneity, neuromodulation mechanisms, biomarker strategies, and key translational challenges, with the goal of positioning microglia as measurable and biologically grounded therapeutic targets.
Parkinson's Disease (PD) is a progressive neurodegenerative disease, which is mainly characterised by the selective depletion of dopaminergic neurons in the substantia nigra and deposition of misfolded aggregates of α-synuclein. It is increasingly being observed that neuroinflammation, mitochondrial dysfunction, and lost neurotrophic support are interacting factors that drive disease progression. The aggregated 1-synuclein triggers an anti-inflammatory phenotype and pro-inflammatory phenotypes in activated microglia, which produce cytokines and reactive oxygen species, aggravating stress in neurons. At the same time, mitochondrial dynamic dysfunction increases oxidative injury, which makes neurons sensitive to degeneration. The low concentration of neurotrophic factors, especially the brain-derived neurotrophic factor (BDNF), impairs the innate ability of the brain to repair itself and maintain its synapses. These pathological processes gradually create a loop of self-feeding, which results in prolonged inflammation, loss of proteostasis, and gradual loss of dopaminergic neurons. This network is interconnected, and understanding it is crucial in the creation of therapies that attempt to restore proteostasis, inhibit inflammation, and increase neurotrophic signalling to delay or prevent PD progression.
Microglia are the resident myeloid cells of the central nervous system, they play essential roles in neural tissue homeostasis, including synaptic pruning, clearance of debris and protein aggregates, and regulation of neuroinflammatory processes. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, microglial activation and chronic glial-driven inflammation contribute substantially to neuronal dysfunction and loss. Beyond these well-characterised functions, recent evidence indicates that microglia can release chromatin-based extracellular traps (microglia extracellular traps, or MiETs), similar to the neutrophil extracellular traps (NETs) observed in peripheral immunity. Microglia ETs are induced by stimuli such as dopamine and microbial infection, dependent or independent of NADPH oxidase/ROS pathways and histone citrullination. This chapter provides a detailed examination of MiET formation, triggers, intracellular signalling, and structural components, as well as contribution to neurodegenerative pathology. Potential mechanisms include amplification of neuroinflammation via extracellular histones and proteases, disruption of the blood-brain barrier and extracellular matrix, synaptic damage, and possible facilitation of spread of misfolded protein aggregates. We situate MiET formation within the broader microglial functional repertoire (phagocytosis, cytokine production, synaptic stripping) and focus on how ET-dominant responses may compromise homeostatic or neuroprotective roles. The chapter reviews evidence from disease models, highlights key gaps and discusses translational implications. Targeting MiET formation or promoting the clearance of MiETs represents promising, yet unexplored, therapeutic avenues in neurodegenerative disease. By focusing on MiETs, this work expands the conceptual framework for microglial pathogenicity and invites future mechanistic and translational research.
The head and neck microbiome plays a critical role in maintaining epithelial homeostasis, regulating immune surveillance, and shaping inflammatory responses that influence carcinogenesis. Increasing evidence suggests that microbial dysbiosis within the oral and gut ecosystems contributes to the initiation and progression of head and neck cancers, particularly oral squamous cell carcinoma. Given that the microbiome is a modifiable risk factor, targeted modulation has emerged as a promising preventive and supportive strategy in HNC. This chapter highlights current knowledge on microbiome-based interventions, including dietary modification, probiotics, prebiotics, postbiotics, synbiotics, fecal microbiota transplantation, and lifestyle changes, with emphasis on their immunomodulatory and anti-inflammatory effects. These approaches aim to restore microbial balance, enhance barrier integrity, reduce chronic inflammation, and strengthen anticancer immune responses. The chapter also discusses mechanistic links between microbial metabolites and immune pathways, the relevance of the oral-gut axis, and emerging evidence connecting microbiome composition with treatment response and toxicity. Finally, key challenges such as inter-individual variability, site-specific microbial niches, safety considerations, and the need for longitudinal and mechanistic studies are addressed. Overall, microbiome modulation represents a promising, precision-oriented avenue for cancer prevention, risk reduction, and survivorship in head and neck oncology, although robust clinical validation is still required.
Macrophages are no longer viewed as transient immune passersby but as integral tissue components that regulate physiological homeostasis. Many resident macrophage populations are seeded prenatally and maintained locally, whereas others are progressively replaced by monocytes, yet the rules governing this divergence remain unclear. The eye provides a natural experiment because anatomically distinct compartments harbor macrophages that perform essential functions but differ sharply in persistence under shared systemic conditions. We synthesize evidence that ocular macrophages regulate matrix homeostasis, lipid metabolism, neuroimmune signaling, vascular support, and barrier control. Despite their physiological importance, macrophage populations with divergent persistence concentrate within millimeters, revealing that local tissue context constrains their self-maintenance durability. We introduce establishment kinetics-an organizing framework defined by when and whether populations acquire durable self-maintenance. Four kinetic classes emerge: permanent (lifelong persistence), juvenile-established (stabilized post-early replacement), adult-established (stabilized post-prolonged replacement), and time-limited (never stabilizing). Across ocular and non-ocular tissues, three principles follow: establishment timing does not predict equilibrium density, resident identity does not ensure durability, and kinetic class is independent of anatomical proximity or immune privilege. This framework shifts focus from origin and replacement to establishment kinetics, providing a predictive structure for understanding resident tissue macrophage behavior across homeostasis, aging, and disease.
Alarmins, a group of molecules that function to signal cell stress or death, are a key regulator of the immune response to localized insults. A tissue type often exposed to challenging conditions is the mucosa. As mucosal tissues commonly serve as a barrier between the host and the external environment, they are frequently exposed to cellular stress in the form of commensal and pathogenic microbes. Furthermore, certain mucosae are also responsible for the uptake of nutrients and other small molecules, and, thus, need to maintain a proper and tightly-regulated level of baseline selective permeability. This dual function requires constant communication between the epithelium and supporting cells formed by the local mucosal immune system, with alarmins playing a key role in this crosstalk. In this chapter, we focus on the two largest and most well-studied mucosal tissue-containing organs: the lung and the gastrointestinal (GI) tract, and present the state-of-the-art knowledge on the regulatory role of alarmins in the proper function or dysfunction of these organs.
Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis and tolerance. While their suppressive function is beneficial in autoimmunity and detrimental in cancer, Tregs also exert essential roles during infections where their functions are nuanced and depend on the context, making their overall role more complex to understand. During infections, Tregs classically dampen excessive immune activation, but this suppression may also allow pathogen persistence. In addition to suppressing excessive inflammation, Tregs can directly promote tissue repair and protection. Recent findings demonstrate that these regenerative properties are also important during infections, where limiting immunopathology and promoting repair are both critical to recovery. Moreover, immune checkpoint molecules such as TIM-3 and TIGIT, classically associated with Treg-mediated suppression, have recently also been suggested to contribute to tissue protection or active repair. Their expression on Tregs raises the possibility that these molecules may support functions beyond immune regulation, potentially participating in the orchestration of tissue repair. This review will focus on how Tregs balance immune suppression and tissue repair during infections, highlighting the importance of these functions for recovery and their potential in developing new therapeutic strategies.
Fungal infections are increasingly recognised as a major threat to global human health, with several million preventable deaths each year now attributable to fungal diseases. Climate change, global pandemics and increased use of antibiotics and immune-suppressing drugs in modern medicine have all contributed towards recent rises in the number of cases of life-threatening fungal infections. To circumvent these trends, it is imperative that we develop a deeper understanding of the immune responses that operate to protect against fungal invasion if we are to develop adjunctive immune-based therapies for these infections. Recent work has already demonstrated how mechanistic insights into antifungal immune responses can yield therapeutic benefits. This chapter covers the major processes, cells and receptors that are required for successful antifungal immune responses, focusing on recent developments that have driven significant new step-changes in our understanding of how these pathogens are detected and removed from the body.
Vaccination is arguably the most effective intervention in reducing the impact of infectious diseases. However, many vaccines provide only partial or transient protection, prompting the need for more effective solutions based on our growing understanding of the pivotal role of CD4+ T follicular helper (Tfh) cells in humoral immunity and how they interact with B cells. Here we review how γδ T cells can boost antibody responses via crosstalk with both Tfh and B cells, which could lead to new adjuvant strategies to improve vaccination efficacy, achieve long-lasting protective immunity and prevent major infectious diseases of global importance.
Macrophages are essential immune cells that arise early during embryogenesis and persist as tissue-resident cells into adulthood. This chapter explores macrophage development, focusing on their roles in the nervous system. We describe their distinct origins from early hematopoietic waves and their differentiation into specialized populations such as microglia and border-associated macrophages (BAMs) in the central nervous system (CNS) as well as nerve-associated macrophages in the peripheral (PNS) and enteric nervous system (ENS). These macrophage populations are crucial for tissue development, maintenance, and repair mediating their effects through intricate cellular communication networks with neighboring cells. Furthermore, we discuss how disruptions in macrophage development - driven by factors such as maternal obesity, stress, or environmental pollutants - can have profound and lasting impacts on neurodevelopmental and neurodegenerative outcomes. Gaining a deeper understanding of these developmental processes offers valuable insights into nervous system integrity and reveals potential therapeutic avenues for mitigating disease-related consequences.
Macrophages are now recognised to be highly heterogeneous, with diverse ontogenies, anatomical locations and characteristics, all of which inform their function. Nerve-associated macrophage subpopulations have been found to exist across tissues, and whilst they appear to have roles in neuronal maintenance and repair, their function is still being elucidated. Although nerve-associated macrophage functions in the Central Nervous System have taken centre-stage, nerve-associated macrophages also interact with peripheral nerves and this field remains relatively understudied. This review discusses recent studies into nerve-associated macrophages across peripheral tissues. These studies identify populations of nerve-associated macrophages in many peripheral tissues, and reveal elegant neuroimmune communication pathways which coordinate functions from infection defence and anti-inflammatory actions to neuronal maintenance for homeostatic tissue function and nerve repair. We highlight nerve-associated macrophage interactions with nerves in peripheral tissues as a rapidly evolving field which could revolutionise our understanding of macrophage function in both homeostasis and disease.
Lipid nanoparticles (LNPs) to deliver messenger RNA (mRNA) have emerged as a transformative strategy in cancer immunotherapy. This chapter explores the pivotal role of LNPs in enabling the efficient and targeted delivery of mRNA for cancer treatment, offering an innovative alternative to traditional therapies. LNPs protect mRNA from degradation, ensure its safe passage into the cytoplasm of target cells, and promote the expression of tumor-specific antigens that can activate the immune system against cancer cells. This chapter covers the fundamental properties of lipid nanoparticles, including their composition, structure, and functional modifications, as well as their mechanism of action in mRNA delivery. It also delves into optimizing LNPs to enhance targeting specificity, reduce toxicity, and improve therapeutic efficacy in cancer immunotherapy. Advances in the design of these nanoparticles, including innovations in surface functionalization and their role in overcoming tumor microenvironment barriers, are discussed. The chapter further examines preclinical and clinical applications of LNP-mediated mRNA cancer vaccines and therapies, highlighting recent successes and case studies. In addition, challenges such as ensuring efficient delivery, managing off-target effects, and addressing potential immune reactions are explored. Finally, future perspectives on developing more advanced LNPs and mRNA therapies, including their potential for personalized cancer treatments, are discussed. By providing an in-depth understanding of the current state and future potential of LNP-mediated mRNA delivery, this chapter aims to offer valuable insights into how this technology is shaping the future of cancer immunotherapy.
