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Central regulation of stress-evoked peripheral immune responses

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Abstract

Stress-linked psychiatric disorders, including anxiety and major depressive disorder, are associated with systemic inflammation. Recent studies have reported stress-induced alterations in haematopoiesis that result in monocytosis, neutrophilia, lymphocytopenia and, consequently, in the upregulation of pro-inflammatory processes in immunologically relevant peripheral tissues. There is now evidence that this peripheral inflammation contributes to the development of psychiatric symptoms as well as to common co-morbidities of psychiatric disorders such as metabolic syndrome and immunosuppression. Here, we review the specific brain and spinal regions, and the neuronal populations within them, that respond to stress and transmit signals to peripheral tissues via the autonomic nervous system or neuroendocrine pathways to influence immunological function. We comprehensively summarize studies that have employed retrograde tracing to define neurocircuits linking the brain to the bone marrow, spleen, gut, adipose tissue and liver. Moreover, we highlight studies that have used chemogenetic or optogenetic manipulation or intracerebroventricular administration of peptide hormones to control somatic immune responses. Collectively, this growing body of literature illustrates potential mechanisms through which stress signals are conveyed from the CNS to immune cells to regulate stress-relevant behaviours and comorbid pathophysiology.

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Fig. 1: CNS innervation of immunologically relevant peripheral tissues.
Fig. 2: Control of peripheral immunity by central stress centres.
Fig. 3: Breakdown of body barriers during stress.

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Acknowledgements

We thank all authors who contributed to the work collected and summarized in this Review. This Review was supported by a Postdoctoral Fellowship from the Canadian Institutes of Health Research (201811MFE-414896-231226), a NARSAD Young Investigator Award from the Brain and Behaviour Research Foundation (30894), and a Pathway to Independence Award from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (K99DK137037) to K.L.C., a research grant from the Cure Alzheimer’s Fund to W.C.P., National Institutes of Health grants R35HL135752, P01HL131478 and 1P01HL142494 to F.K.S., and R01MH104559 and R01MH127820 to S.J.R. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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K.L.C. and S.J.R. researched data for the article and wrote the article. All authors contributed substantially to the discussion of content and reviewed and/or edited the manuscript before submission.

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Glossary

Chemogenetics

An approach in which specific cellular pathways are activated or inhibited using engineered protein receptors that respond to previously unrecognized small molecules.

Chemokines

Chemotactic cytokines that stimulate the migration of cells.

Cytokines

Secreted proteins that act as signalling molecules for the immune system.

Granulocyte

Leukocytes containing cytoplasmic secretory granules such as neutrophils, basophils and eosinophils.

Leukocytes

A type of blood cell made in the bone marrow and found within blood and lymphoid tissue as part of the immune system.

Lymphocytopenia

A reduction in the number of lymphocytes in the blood.

Lymphopoiesis

The production of lymphocytes from progenitor cells.

Monocytosis

An increase in the number of monocytes in the blood.

Myelopoiesis

The production of myeloid cells from progenitor cells.

Neutrophilia

An increase in the number of neutrophils in the blood.

Optogenetics

An approach in which light-sensitive ion channels, pumps or enzymes are used to regulate the activity of specific neurons in the brain or periphery.

Plasma cells

Effector B lymphocytes that produce antibodies.

Resilience

The ability to maintain normal physiological and behavioural function in the face of severe stress.

Reward

A positive emotional stimulus. In psychological terms, a reward is reinforcing — it promotes repeated responses to obtain the same stimulus.

Splenomegaly

An enlargement of the spleen.

Susceptible

Having increased vulnerability to succumb to the deleterious effects of stress.

Ventral tegmental area

VTA. A ventral midbrain site containing dopaminergic neurons that are an essential component of the reward circuitry in the brain.

Viral tracing

The use of trans-synaptic self-replicating viruses to identify neural pathways.

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Chan, K.L., Poller, W.C., Swirski, F.K. et al. Central regulation of stress-evoked peripheral immune responses. Nat. Rev. Neurosci. 24, 591–604 (2023). https://doi.org/10.1038/s41583-023-00729-2

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