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