An integrated cytokine and kynurenine network as the basis of neuroimmune communication

Abstract

Two of the molecular families closely associated with mediating communication between the brain and immune system are cytokines and the kynurenine metabolites of tryptophan. Both groups regulate neuron and glial activity in the central nervous system (CNS) and leukocyte function in the immune system, although neither group alone completely explains neuroimmune function, disease occurrence or severity. This essay suggests that the two families perform complementary functions generating an integrated network. The kynurenine pathway determines overall neuronal excitability and plasticity by modulating glutamate receptors and GPR35 activity across the CNS, and regulates general features of immune cell status, surveillance and tolerance which often involves the Aryl Hydrocarbon Receptor (AHR). Equally, cytokines and chemokines define and regulate specific populations of neurons, glia or immune system leukocytes, generating more specific responses within restricted CNS regions or leukocyte populations. In addition, as there is a much larger variety of these compounds, their homing properties enable the superimposition of dynamic variations of cell activity upon local, spatially limited, cell populations. This would in principle allow the targeting of potential treatments to restricted regions of the CNS. The proposed synergistic interface of ‘tonic’ kynurenine pathway affecting baseline activity and the superimposed ‘phasic’ cytokine system would constitute an integrated network explaining some features of neuroimmune communication. The concept would broaden the scope for the development of new treatments for disorders involving both the CNS and immune systems, with safer and more effective agents targeted to specific CNS regions.

The immunomodulatory mechanism of acupuncture treatment for ischemic stroke: research progress, prospects, and future direction

“…Studies have shown that cytokines are the core mediators of neuroimmune regulatory mechanisms ( 109 , 110 ). Acupuncture bidirectionally modulates the release of immune cytokines, forming a complex network with multiple effects on IS.…”

Vertebral Subluxation and Systems Biology: An Integrative Review Exploring the Salutogenic Influence of Chiropractic Care on the Neuroendocrine-Immune System

“…In sum, current evidence demonstrates that chiropractic care can impact a range of immune and neuroimmune biomarkers, potentially explaining the observations of immune function improvements reported by field practitioners in case studies. The possible biological mechanisms by which VS may impact known NEI modulation pathways are multiple and overlapping, including but not limited to evoking functional changes within the cholinergic anti-inflammatory pathway [ 278 ], promoting population shifts within leukocyte populations [ 279 ], activation of immune system effectors [ 239 ], and indirect effects on immune function as would be mediated by cortisol flux [ 230 , 280 ]. Future research should be directed at detailed characterization of the effects of VS and its reduction or resolution on the above parameters, in relation to overall clinical immune outcomes and in different populations, with the goal of enhancing the current understanding of the relationship between chiropractic care and immune health and adaptability.…”

The Tryptophan and Kynurenine Pathway Involved in the Development of Immune-Related Diseases

“…Cytokines and kynurenines are closely associated with mediating the communication between the brain and the immune system, which could regulate the neuron and/or glial activity in the central nervous system (CNS), as well as the function of the immune system within a combined network. This concept would broaden the scope for the development of new treatments for disorders that involve immune systems with harmless and/or more active agents [ 27 ]. During inflammation, pro-inflammatory cytokines, mainly tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), may increase the catabolism of tryptophan by encouraging the expression of indoleamine 2,3-dioxygenase [ 28 ].…”