Therapeutic Implications of Brain-Immune Interactions: Treatment in Translation

Abstract

A wealth of data has been amassed that details a complex, yet accessible, series of pathways by which the immune system, notably inflammation, can influence the brain and behavior. These data have opened the window to a diverse array of novel targets whose potential efficacy is tied to specific neurotransmitters and neurocircuits as well as specific behaviors. What is clear is that the impact of inflammation on the brain cuts across psychiatric disorders and engages dopaminergic and glutamatergic pathways that regulate motivation and motor activity as well as the sensitivity to threat. Given the ability to identify patient populations with increased inflammation, the precision of interventions can be further tuned, in conjunction with the ability to establish target engagement in the brain through the use of multiple neuroimaging strategies. After a brief overview of the mechanisms by which inflammation affects the brain and behavior, this review examines the extant literature on the efficacy of anti-inflammatory treatments, while forging guidelines for future intelligent clinical trial design. An examination of the most promising therapeutic strategies is also provided, along with some of the most exciting clinical trials that are currently being planned or underway.

Figure 1

Hitting the sweet spot—above all do no harm. Cytokines play pivotal roles in multiple aspects of neuronal integrity including long-term potentiation, synaptic remodeling, neurogenesis, learning, memory, and possibly the response to treatments such as antidepressants. Thus, dose–response studies using anticytokine therapies must focus on those patients with evidence of excessive cytokine activation to find the optimal dose of drug that limits the detrimental effects of cytokines on brain function, while leaving their indispensible activities intact. As noted, there may be issues of the timing of these interventions as well.

Figure 2

Causes and consequences of chronic inflammation. A wide array of genetic, developmental, lifestyle, and disease factors conspire to lead to chronic, nonresolving inflammation that has been shown to impact fundamental pathways to psychiatric pathology including the metabolism of neurotransmitters and other neuromodulators as well as neuroendocrine function, ultimately leading to distinct changes in behavior that are rooted in evolutionarily derived responses to illness. Dysregulation of immune (eg, T cell) responses in turn can exacerbate inflammation as well as affect the brain and behavior.

Figure 3

Neurotransmitter targets for therapeutic development in psychiatric disorders. Aside from the more obvious immune targets of therapeutic interventions (eg, cytokines and their receptors, adhesion molecules, and chemokines), there are a host of metabolic and immunologic signaling pathways that mediate the downstream effects of inflammation on neurotransmitter systems including the synthesis, reuptake and release of dopamine, glutamate, and serotonin. Moreover, there is increasing interest in the role of the kynurenine pathway in multiple aspects of the impact of inflammation on excitotoxicity and neurotransmitter metabolism. 5HT: serotonin; 5HTT: serotonin transporter; BH4: tetrahydrobiopterin; DA: dopamine; EAAT: excitatory amino acid transporter; Glu: glutamate; IDO: indoleamine 2,3 dioxygenase; IL: interleukin; KA: kynurenic acid; KAT: kynurenine aminotransferase; KMO: kynurenine 3-monooxygenase; KYN: kynurenine; MAPK: mitogen-activated protein kinase; nAChR: nicotinic acetylcholine receptor; NF-κB: nuclear factor-κB; NMDAR: N-methyl-D-aspartate receptor; Phe: phenylalanine; QA: quinolinic acid; TH: tyrosine hydroxylase; TNF: tumor necrosis factor; TRP: tryptophan; Tyr: tyrosine.

Figure 4

Neuroendocrine and immunomodulatory targets for therapeutic development in psychiatric disorders. Neuroendocrine and immune pathways can serve as additional targets to modulate the immune system leading to neuroprotective and immunoregulatory responses involving the elaboration of growth factors such as BDNF and T-cell subtypes (eg, Tregs and ChAT+ T cells) with anti-inflammatory properties. These targets include administration of glucocorticoids that support trafficking of immunomodulatory, IL-4-producing T cells to the brain as well as electroceutical interventions involving stimulation of the efferent vagus to induce Ach-producing T cells that, via the α7 nAChR, can inhibit NF-κB and TLR-4 expression. Finally, infectious agents and manipulations of the microbiome can foster the development of Tregs that have a multiplicity of anti-inflammatory effects. ACh: acetylcholine; BDNF: brain-derived neurotrophic factor; CD: cluster of differentiation; ChAT: choline acetyltransferase; CTLA: cytotoxic T-lymphocyte-associated protein; GR: glucocorticoid receptor; IFN: interferon; IL: interleukin; M: macrophage; M. vaccae: Mycobacterium vaccae; nAChR: nicotinic acetylcholine receptor; NF-κB: nuclear factor-κB; TGF: transforming growth factor; TLR: Toll-like receptor; Tregs: T regulatory cells.