Elsevier

Brain Research Bulletin

Volume 172, July 2021, Pages 61-78
Brain Research Bulletin

Review
Bidirectional communication between mast cells and the gut-brain axis in neurodegenerative diseases: Avenues for therapeutic intervention

https://doi.org/10.1016/j.brainresbull.2021.04.010Get rights and content

Highlights

  • Mast cells act as a “tuning” of neuroimmune signaling.

  • Gut microbiota regulate neuroimmune networks and brain activity.

  • Inflammatory mediators from mast cell in gut and brain promote neuroinflammation.

  • Mast cells mediating gut-brain communication: an emerging therapeutic intervention.

Abstract

Although the global incidence of neurodegenerative diseases has been steadily increasing, especially in adults, there are no effective therapeutic interventions. Neurodegeneration is a heterogeneous group of disorders that is characterized by the activation of immune cells in the central nervous system (CNS) (e.g., mast cells and microglia) and subsequent neuroinflammation. Mast cells are found in the brain and the gastrointestinal tract and play a role in “tuning” neuroimmune responses. The complex bidirectional communication between mast cells and gut microbiota coordinates various dynamic neuro-cellular responses, which propagates neuronal impulses from the gastrointestinal tract into the CNS. Numerous inflammatory mediators from degranulated mast cells alter intestinal gut permeability and disrupt blood-brain barrier, which results in the promotion of neuroinflammatory processes leading to neurological disorders, thereby offsetting the balance in immune-surveillance. Emerging evidence supports the hypothesis that gut-microbiota exert a pivotal role in inflammatory signaling through the activation of immune and inflammatory cells. Communication between inflammatory cytokines and neurocircuits via the gut-brain axis (GBA) affects behavioral responses, activates mast cells and microglia that causes neuroinflammation, which is associated with neurological diseases. In this comprehensive review, we focus on what is currently known about mast cells and the gut-brain axis relationship, and how this relationship is connected to neurodegenerative diseases. We hope that further elucidating the bidirectional communication between mast cells and the GBA will not only stimulate future research on neurodegenerative diseases but will also identify new opportunities for therapeutic interventions.

Introduction

The rising prevalence of neurodegenerative diseases is a challenging global problem for the scientific community. Neurodegenerative diseases affect millions of people worldwide, and affect aging communities more than any other demographic (Partridge et al., 2018; Erkkinen et al., 2018; Trojanowski and Hampel, 2011; Katsnelson et al., 2016). The most prevalent neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), are fatal conditions that are associated with the death of neurons in the brain. During the past several decades, the scientific community has been struggling to develop effective treatments for deadly neurodegenerative diseases. However, the precise molecular mechanisms that contribute to neurodegenerative diseases remains largely ambiguous and poorly understood. Emerging studies have identified that an imbalance in the fine-tuning of inflammatory and neuroimmune mechanisms can promote the progression of neurodegenerative disease (Scheiblich et al., 2020).

Neuroinflammation is a unique feature of neurodegenerative diseases (Stephenson et al., 2018; Guzman-Martinez et al., 2019; Wohleb and Godbout, 2013). Mast cells (MCs)—also known as inflammatory effector cells—are immune cells found in the brain that play a critical role in the neuroinflammation that contributes to neurodegenerative diseases (Mittal et al., 2019; Hendriksen et al., 2017). MCs act as “master regulators” of the immune system and play an important role in the mechanisms of inflammatory and neuroimmune networks (Traina, 2017). A number of studies have reported that MCs can regulate innate and adaptive immunity through the secretion of numerous mediators, including neurotransmitters, cytokines, chemokines, lipid-derived factors, neuropeptides, and hormones (Galli et al., 2005a, 2008; Marshall and Jawdat, 2004; Forsythe, 2019). These mediators influence immunoregulation and have diverse implications in health and disease (Tsai et al., 2011). MCs can communicate directly with immune cells in the brain (microglia, myeloid cells, dendritic cells, T cells, B cells, and natural killer [NK] cells) and modulate key signaling networks that regulate the physiological function of the nervous system, such as neuronal sensitization, synaptic plasticity, and cellular homeostasis (da Silva et al., 2014; Skaper et al., 2014; Galli et al., 2011; Wernersson and Pejler, 2014). In addition, MCs also modulate and influence neuronal activity, emotional behaviors, and synaptic transmission associated with neuroimmune links (Nautiyal et al., 2008), and may regulate N-methyl-D-aspartate (NMDA)-mediated synaptic transmission and exocytosis in hippocampal neurons (Flores et al., 2019).

MCs act as a master regulator of the neuro-immuno-endocrine super complex networks that influence innate and adaptive immune responses and coordinate with multiple physiological processes, and thus promote the bidirectional relationship between the nervous, immune, and endocrine systems. Interestingly, intestinal MCs can interact with neuronal and endocrine components by communicating via the gut-brain axis (GBA), thereby modulating the immune response in the brain and the neuroinflammation associated with neurodegeneration (Traina, 2017).Recent evidence shows that the GBA allows gut microbiota to influence the enteric nervous system, controlling the receptors, mediators, and brain-resident immune cells (MCs) that facilitate cross-talk between nervous, immune, and endocrine systems (Girolamo et al., 2017; Traina, 2019; Farzi et al., 2018).

The GBA refers to the central biochemical signaling pathway that facilitates bidirectional communication between the gut and the brain, and involves neural, endocrine, and inflammatory signals. In addition, the GBA controls brain homeostasis and regulates cognitive and emotional functions via gut microbiota (Farzi et al., 2018; Carabotti et al., 2015a; Liang et al., 2018), which communicate directly with the brain via immune cells (e.g., MCs, glia, etc.) and have been shown to play a role in maintaining the immune system, regulating neuroimmune networks, and modifying distinct neurocircuits (Ma et al., 2019; Rothhammer et al., 2016; Keita and Söderholm, 2010). It has been shown that the dysregulation of gut microbiota can contribute to the pathogenesis of neurodegenerative diseases (Dinan and Cryan, 2017; Quigley, 2017; Ambrosini et al., 2019). While research supports the theory that MCs maintain neuroimmune signaling and act as an intermediate player in the cross‐talk interaction between the GBA and the neuroimmune system (Forsythe, 2019; Vojdani, 2016), the precise underlying mechanisms of the relationship between the gut-brain axis and the neuroimmune system remains unknown.

Therefore, the main purpose of this comprehensive review is to focus on our current understanding of the bidirectional link between MCs and the GBA during neurodegeneration. This paper also critiques recent advances in our understanding of the role of MCs in the neuroimmune and brain-gut signaling axis in relation to current therapeutic interventions of neurodegenerative diseases.

Section snippets

Materials and methods

We used Goggle Scholar, PubMed, and publons, from the year 1988–2021. Then, we comprehensively summarized the bidirectional communication between mast cells and the GBA with therapeutic intervention in neurological diseases. Keywords were used to determine literature search, including “MCs”, “GBA”, “gut microbiota”, “neurodegenerative disease”, “neuroinflammation”, “inflammatory cytokines and neurocircuits”, “neuroimmune and enteroendocrine signaling”, “MCs activation”, “neuroactive molecules”,

Mast cells: origin and activation

MCs are hematopoietic-lineage cells that originate from bone marrow and are derived from CD34+/CD117+ progenitor cells that spread through the bloodstream and migrate to different tissues (Dahlin and Hallgren, 2015; Ribatti, 2016). MCs are generally localized to exterior layers and barriers such as mucosal membranes, vascular surfaces, and epithelial borders. The CD34+/CD117+ progenitor cells differentiate into mature MCs in the presence of specific growth factors and biomolecules. MCs release

Reciprocal communication between gut microbiota and MCs

Gut microbiota maintain bidirectional communication between the GBA and MCs via immune, neural, and metabolic pathways. Gut microbiota play a crucial role in immune maturation, stimulation, neuroimmune signaling, and brain activity (Traina, 2017; Choi et al., 2013; Cryan and Dinan, 2015a; Cussotto et al., 2018; Kawahara, 2010). The brain may also influence the composition and function of gut microbiota by altering the intestinal permeability of epithelia, which can lead to the stimulation of an

Integral roles of mast cells in the neuro-immune response network

MCs—best known as potent proinflammatory effector cells—are important brain-resident immune cells in the meninges and the nervous system, are associated with the abluminal surface of the BBB, and are tightly apposed to microvessels in the neurovascular unit (NVU). MCs regulate immune homeostasis via the suppression of multiple immune responses that are associated with interleukin-10 production from CD5 (+) B and FoxP3+ Treg cells (Kim et al., 2015; Betto et al., 2017). MCs may play a role in

Gut microbiota involving neuro-immune network

Gut microbiota—formerly called gut flora—are crucial modulators of brain development and activity and are also required for neuroimmune cell development and stimulation. Mounting evidence suggests that imbalances in the gut microbiota may impair the homeostasis of neuroimmune responses, thereby leading to the development of chronic inflammation, autoimmune diseases, cancer, and neurodegenerative diseases (Sekirov et al., 2010; Caballero-Villarraso et al., 2017). Thus we need to better

Alzheimer’s disease (AD)

AD is an incurable progressive neurodegenerative disease that is characterized by the deterioration of memory and cognitive dysfunction. In the past decade, research has observed the pathology of AD in AD patients, which includes an increase in the level of extracellular amyloid-β (Aβ) plaque deposits, hyperphosphorylated tau pathology, rapid loss of neurons and synapses, declines in dopaminergic, serotonergic, and noradrenergic systems, and alterations in neurotransmitter systems (Spires-Jones

Bidirectional relationship between the GBA and MCs in neurodegenerative diseases

Gut microbiota regulate and influence brain function, and may also contribute to brain dysfunction in various neurological diseases through the kynurenine pathway (KP) of tryptophan (Trp) degradation (Maddison and Giorgini, 2015). The KP is a major pathway of L-tryptophan catabolism, and maintains the production of numerous neuroactive metabolites, including serotonin, kynurenic acid, 3-hydroxykynurenine, and quinolinic acid (Guillemin, 2012). These metabolites are regulated by an enzymatic

MCs contribute to GBA mediated neurodegenerative diseases: a promising therapeutic target

Recent research approaches have demonstrated that activation of MCs initiates the release of pro-inflammatory mediators which disrupt BBB and neurovascular dysfunction that is linked with GBA, leading to neuroinflammation and brain damage (Traina, 2017; Dong et al., 2014a; Kempuraj et al., 2019; Tohidpour et al., 2017; Liebner et al., 2018).

Pro-inflammatory cytokines are pleiotropic molecules that play an important role in neurological diseases and the pathogenesis of inflammatory bowel disease

The relationship between proinflammatory cytokines and MCs activation in tolerance and inflammation

Intense research on MCs over the past years, MCs are undoubtedly required to maintain inflammation or tolerance, particularly in the immune system (de Vries and Noelle, 2010; Krystel-Whittemore et al., 2016b). There is growing evidence that MCs act as “immune sensors” and are critical regulatory cells involved in innate and adaptive immunity (Tete et al., 2012; Cardamone et al., 2016; Palker et al., 2010). These cells can recruit and regulate other innate and adaptive immune systems by

Conclusion and future perspectives

In recent years, there has been a rapid and comprehensive expansion in our knowledge regarding the role of bidirectional communication between MCs and the GBA in neurodegenerative diseases. However, some questions remain unanswered. Addressing research directions regarding molecular, cellular, and neuroimmune network-related aspects of bidirectional communication between MCs and the GBA is will be both rewarding and challenging. MCs may be a unique therapeutic target because they directly

Declaration of Competing Interest

The authors report no declarations of interest.

Acknowledgments

This project was sponsored by the grants from the National Natural Science Foundation of China (No 81801061, 81701375), a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). We would like to special thank Prof. Xin Wang, Lydia Becker Institute of Immunology and Inflammation of the University of Manchester for helpful suggestion and critically reading of our manuscript.

References (348)

  • E. Betto et al.

    Mast cells contribute to autoimmune diabetes by releasing interleukin-6 and failing to acquire a tolerogenic IL-10+ phenotype

    Clin. Immunol.

    (2017)
  • K. Brockow et al.

    IL-6 levels predict disease variant and extent of organ involvement in patients with mastocytosis

    Clin. Immunol.

    (2005)
  • C. Cai et al.

    Mast cells play a critical role in the systemic inflammatory response and end-organ injury resulting from trauma

    J. Am. Coll. Surg.

    (2011)
  • L. Calvo-Barreiro et al.

    Combined therapies to treat complex diseases: the role of the gut microbiota in multiple sclerosis

    Autoimmun. Rev.

    (2018)
  • C. Cardamone et al.

    Mast cells as effector cells of innate immunity and regulators of adaptive immunity

    Immunol. Lett.

    (2016)
  • G.H. Caughey

    Mast cell proteases as pharmacological targets

    Eur. J. Pharmacol.

    (2016)
  • M. Chai et al.

    Non-cell-Autonomous neurotoxicity in parkinson’s disease mediated by astroglial α-Synuclein

    Stem Cell Reports

    (2019)
  • Y.X. Chao et al.

    Mesenchymal stem cell transplantation attenuates blood brain barrier damage and neuroinflammation and protects dopaminergic neurons against MPTP toxicity in the substantia nigra in a model of Parkinson’s disease

    J. Neuroimmunol.

    (2009)
  • E.M. Chastain et al.

    The role of antigen presenting cells in multiple sclerosis

    Biochim. Biophys. Acta

    (2011)
  • S.S. Chavan et al.

    Mechanisms and therapeutic relevance of neuro-immune communication

    Immunity

    (2017)
  • L.H. Cheng et al.

    Psychobiotics in mental health, neurodegenerative and neurodevelopmental disorders

    J. Food Drug Anal.

    (2019)
  • H.W. Choi et al.

    Salmonella typhimurium impedes innate immunity with a mast-cell-suppressing protein tyrosine phosphatase, SptP

    Immunity

    (2013)
  • P. Conti et al.

    Microglia and mast cells generate proinflammatory cytokines in the brain and worsen inflammatory state: suppressor effect of IL-37

    Eur. J. Pharmacol.

    (2020)
  • N. Couturier et al.

    Mast cell transcripts are increased within and outside multiple sclerosis lesions

    J. Neuroimmunol.

    (2008)
  • S. Cussotto et al.

    The neuroendocrinology of the microbiota-gut-Brain Axis: a behavioural perspective

    Front. Neuroendocrinol.

    (2018)
  • J.S. Dahlin et al.

    Mast cell progenitors: origin, development and migration to tissues

    Mol. Immunol.

    (2015)
  • J.S. Dahlin et al.

    Lin- CD34hi CD117int/hi FcεRI+ cells in human blood constitute a rare population of mast cell progenitors

    Blood

    (2016)
  • A. De Virgilio et al.

    Parkinson’s disease: autoimmunity and neuroinflammation

    Autoimmun. Rev.

    (2016)
  • V.C. de Vries et al.

    Mast cell mediators in tolerance

    Curr. Opin. Immunol.

    (2010)
  • T.G. Dinan et al.

    The microbiome-gut-Brain Axis in health and disease

    Gastroenterol. Clin. North Am.

    (2017)
  • P. Draber et al.

    Signal transduction and chemotaxis in mast cells

    Eur. J. Pharmacol.

    (2016)
  • A. Dudeck et al.

    Mast cells as protectors of health

    J. Allergy Clin. Immunol.

    (2019)
  • P. Esposito et al.

    Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells

    Brain Res.

    (2001)
  • A. Farzi et al.

    Gut Microbiota and the Neuroendocrine System

    Neurotherapeutics

    (2018)
  • V.D. Felice et al.

    Microbiota-gut-brain signalling in Parkinson’s disease: implications for non-motor symptoms

    Parkinsonism Relat. Disord.

    (2016)
  • P. Forsythe

    Mast cells in neuroimmune interactions

    Trends Neurosci.

    (2019)
  • J.A. Foster et al.

    Stress & the gut-brain axis: regulation by the microbiome

    Neurobiol. Stress

    (2017)
  • M.G. Frank et al.

    Immunization with Mycobacterium vaccae induces an anti-inflammatory milieu in the CNS: attenuation of stress-induced microglial priming, alarmins and anxiety-like behavior

    Brain Behav. Immun.

    (2018)
  • C.C. Aguiar et al.

    Oxidative stress and epilepsy: literature review

    Oxid. Med. Cell. Longev.

    (2012)
  • M.S. Airaksinen et al.

    Neurofibrillary tangles and histamine-containing neurons in Alzheimer hypothalamus

    Agents Actions

    (1991)
  • H. Ali

    Mas-related G protein coupled receptor-X2: a potential new target for modulating mast cell-mediated allergic and inflammatory diseases

    J. Immunobiol.

    (2016)
  • K.A. Almehmadi et al.

    Increased expression of miR-155p5 in amygdala of children with autism Spectrum disorder

    Autism Res.

    (2020)
  • K.D. Alysandratos et al.

    Neurotensin and CRH interactions augment human mast cell activation

    PLoS One

    (2012)
  • K.D. Alysandratos et al.

    Neurotensin and CRH interactions augment human mast cell activation

    PLoS One

    (2012)
  • Y.M. Ambrosini et al.

    The gut-brain Axis in neurodegenerative diseases and relevance of the canine model: a review

    Front. Aging Neurosci.

    (2019)
  • T. Antonelli et al.

    Neurotensin enhances endogenous extracellular glutamate levels in primary cultures of rat cortical neurons: involvement of neurotensin receptor in NMDA induced excitotoxicity

    Cereb. Cortex

    (2004)
  • A.K. Arya et al.

    Brain-gut axis after stroke

    Brain Circ.

    (2018)
  • S. Athari Nik Azm et al.

    Lactobacilli and bifidobacteria ameliorate memory and learning deficits and oxidative stress in β-amyloid (1-42) injected rats

    Appl. Physiol. Nutr. Metab.

    (2018)
  • D.R. Beers et al.

    CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS

    Proc Natl Acad Sci U S A

    (2008)
  • C. Benoist et al.

    Mast cells in autoimmune disease

    Nature

    (2002)
  • Cited by (0)

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