Journal of Clinical & Experimental Neuroimmunology
Open Access

Neuroimmunology; Immune cells; Neurons; Neuroinflammation; Cytokines; Microglia; Synaptic plasticity; Neurological disorders

Introduction

The concept of the brain as an immunologically privileged site has been revised significantly in recent decades. It is now well established that the immune system and the nervous system engage in constant bidirectional communication, influencing each other’s function in both health and disease. This neuroimmune cross-talk involves a complex network of signaling molecules, including cytokines, chemokines, and neurotransmitters, as well as direct cell-to-cell interactions. Understanding these interactions is crucial for deciphering the mechanisms underlying various neurological and psychiatric disorders, where immune system dysregulation plays a significant role. This review aims to explore the key mechanisms of communication between immune cells and neurons, highlighting their roles in both physiological processes and pathological conditions.

Results

Communication between immune cells and neurons occurs through several key mechanisms. Cytokines, small signaling proteins produced by both immune and non-immune cells, are crucial mediators of neuroimmune communication. They can bind to receptors on neurons and immune cells, triggering intracellular signaling cascades that influence cell function. Pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, can exert both neurotoxic and neuroprotective effects depending on the context and concentration. For instance, while acute, controlled release of these cytokines can promote neuronal survival and synaptic plasticity, chronic or excessive production can contribute to neuronal damage and cognitive decline. Conversely, anti-inflammatory cytokines, such as IL-10 and TGF-β, generally promote neuronal survival and tissue repair. Chemokines, another class of signaling molecules, are chemoattractant cytokines that guide the migration of immune cells to specific locations. In the CNS, chemokines play a critical role in regulating the recruitment of peripheral immune cells to the brain during inflammation. However, dysregulated chemokine signaling can contribute to excessive immune cell infiltration and exacerbate neuroinflammation. Direct cell-to-cell contact also plays a significant role in neuroimmune communication. Microglia, the resident immune cells of the CNS, are in constant contact with neurons, monitoring their activity and responding to changes in the microenvironment. Microglia can phagocytose cellular debris, prune synapses, and release trophic factors that support neuronal survival and function. However, in pathological conditions, microglia can become chronically activated, releasing pro-inflammatory cytokines and contributing to neurotoxicity. Astrocytes, another type of glial cell, also interact closely with both neurons and immune cells. They can release cytokines and chemokines, modulate synaptic transmission, and regulate the blood-brain barrier (BBB), which controls the entry of peripheral immune cells into the CNS. Neurons themselves can also actively communicate with immune cells. They can express receptors for cytokines and chemokines, allowing them to respond directly to immune signals. Furthermore, neurons can release neurotransmitters that can influence immune cell activity. For example, acetylcholine, a neurotransmitter involved in learning and memory, can suppress the production of pro-inflammatory cytokines by immune cells. The interactions between immune cells and neurons play crucial roles in both physiological and pathological conditions. In the healthy brain, these interactions are essential for maintaining homeostasis, supporting synaptic plasticity, and regulating neurogenesis. For instance, microglia play a vital role in synaptic pruning during development and in maintaining synaptic function in the adult brain. However, in pathological conditions, such as neurodegenerative diseases, stroke, and autoimmune disorders, dysregulated neuroimmune communication can contribute to disease pathogenesis. In Alzheimer’s disease (AD), chronic neuroinflammation driven by activated microglia and astrocytes contributes to amyloid-β plaque formation, neurofibrillary tangle accumulation, and neuronal loss [1]. In Parkinson’s disease (PD), neuroinflammation plays a key role in the degeneration of dopaminergic neurons in the substantia nigra [2]. In multiple sclerosis (MS), autoreactive immune cells infiltrate the CNS and attack myelin, the protective sheath surrounding nerve fibers, leading to demyelination and neurological deficits [3]. In stroke, the initial inflammatory response is crucial for clearing cellular debris and initiating tissue repair, but excessive inflammation can exacerbate neuronal damage [4]. These interactions are also relevant in psychiatric disorders. Growing evidence suggests a role for neuroinflammation in the pathogenesis of depression, schizophrenia, and autism spectrum disorder [5]. For example, elevated levels of pro-inflammatory cytokines have been observed in the blood and brain of individuals with depression, suggesting a link between inflammation and mood disorders. Recent studies have also investigated the impact of peripheral immune responses on brain function and behavior. Systemic inflammation, triggered by infections or other peripheral stimuli, can influence neuroinflammation and contribute to cognitive and behavioral changes [6]. This highlights the importance of considering the interplay between peripheral and central immune responses in understanding brain health and disease. Furthermore, genetic factors can influence the susceptibility to neuroinflammatory processes and the interactions between immune cells and neurons. Polymorphisms in genes encoding cytokines, chemokines, receptors, and other immune-related molecules can affect the magnitude and duration of the inflammatory response [7]. For instance, variations in the TREM2 gene, which encodes a microglial receptor, have been linked to increased risk of AD [8]. Emerging research also explores the role of the gut microbiome in modulating neuroimmune communication. The gut microbiota can influence systemic inflammation and subsequently impact neuroinflammation and brain function [9]. Dysbiosis, an imbalance in the gut microbiota, has been linked to increased inflammation and altered brain function. Finally, therapeutic strategies targeting neuroimmune interactions are being actively investigated. These strategies include targeting specific cytokines or chemokines, modulating microglial activity, and promoting the resolution of inflammation [10].  

Discussion

The findings summarized in this review highlight the complex and dynamic nature of the interactions between immune cells and neurons. These interactions play crucial roles in both physiological and pathological conditions, influencing brain development, function, and susceptibility to disease. Understanding the specific mechanisms involved in neuroimmune communication is essential for developing effective therapeutic strategies for neurological and psychiatric disorders.  

Conclusion

The interplay between the immune and nervous systems is a critical area of research with significant implications for human health. Further investigation into the complex interactions between immune cells and neurons will provide valuable insights into the pathogenesis of various neurological and psychiatric disorders, paving the way for the development of novel therapeutic interventions.

1. Simona S, Ioana AC, Aurora ST, Daniel D (2019) Cognitive-behavioral therapy (CBT) for generalized anxiety disorder: Contrasting various CBT approaches in a randomized clinical trial. J Clin Psychol 75: 1188-1202.

               Indexed at, Google Scholar, Crossref

2. Julia DK, Bruin ED, Gradisar M (2019) Cognitive Behavioral Therapy for Insomnia (CBT-i) in School-Aged Children and Adolescents. Sleep Med Clin 14: 155-165.

               Indexed at, Google Scholar, Crossref

3. Daniel D, Carmen C, Silviu M, Cristina M, Simona S (2018) 50 years of rational-emotive and cognitive-behavioral therapy: A systematic review and meta-analysis. J Clin Psychol 74: 304-318.

              Indexed at, Google Scholar, Crossref

4. Jennifer JT, Olivia BW, Kamryn TE (2018) Cognitive-behavioral treatment of avoidant/restrictive food intake disorder. Curr Opin Psychiatry 31: 425-430.

               Indexed at, Google Scholar, Crossref

5. Steffen M, Philipp KJ, Paul HL, Stephanie M (2019) Metacognitive and cognitive-behavioral interventions for psychosis: new developments. Dialogues Clin Neurosci 21: 309-307.

              Indexed at, Google Scholar, Crossref

6. Schwartz K, Boles BR (2013)  Microbial amyloids—Functions and interactions within the host.Curr Opin Microbiol 16:93–99 .

             Indexed at, Google Scholar, Crossref

7. Wang WY, Tan MS, Yu JT, Tan L (2015)  Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease.Ann Transl Med3:136.

              Indexed at, Google Scholar, Crossref

8. Schwab C, Klegeris A, McGeer PL (2010) Inflammation in transgenic mouse models of neurodegenerative disorders.Biochim Biophys Acta1802:889-902.

              Indexed at, Google Scholar, Crossref

9. Lin L, Zheng LJ, Zhang LJ (2018)  Neuroinflammation, Gut Microbiome, and Alzheimer’s Disease.Mol Neurobiol 55:8243-8250.

       Indexed at, Google Scholar, Crossref

10. Julia DK, Bruin ED, Gradisar M (2019) Cognitive Behavioral Therapy for Insomnia (CBT-i) in School-Aged Children and Adolescents. Sleep Med Clin 14: 155-165.

               Indexed at, Google Scholar, Crossref