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Neuroanatomy of the spleen: Mapping the relationship between sympathetic neurons and lymphocytes.

ABSTRACT: The nervous system plays a profound regulatory role in maintaining appropriate immune responses by signaling to immune cells. These immune cells, including B- and T-cells, can further act as intermediary messengers, with subsets of B- and T-cells expressing choline acetyltransferase (ChAT), the enzyme required for acetylcholine (ACh) synthesis. Neural control of ACh release from ChAT+ T-cells can have powerful immune implications, regulating lymphocyte trafficking, inflammation, and prevent death due to experimental septic shock. Although ACh release from T-cells has been proposed to occur following norepinephrine (NE) released from sympathetic nerve terminals in the spleen, it is unknown how this communication occurs. While it was proposed that tyrosine hydroxylase (TH+) axons form synapse-like structures with ChAT+ T-cells, there is scant evidence to support or refute this phenomenon. With this in mind, we sought to determine the relative abundance of ChAT+ B- and T-cells in close proximity to TH+ axons, and determine what factors contribute to their localization in the spleen. Using confocal microscopy of tissue sections and three-dimensional imaging of intact spleen, we confirmed that ChAT+ B-cells exceed the number of ChAT+ T-cells, and overall few ChAT+ B- or T-cells are located close to TH+ fibers compared to total numbers. The organized location of ChAT+ lymphocytes within the spleen suggested that these cells were recruited by chemokine gradients. We identified ChAT+ B- and T-cells express the chemokine receptor CXCR5; indicating that these cells can respond to CXCL13 produced by stromal cells expressing the ?2 adrenergic receptor in the spleen. Our findings suggest that sympathetic innervation contributes to organization of ChAT+ immune cells in the white pulp of the spleen by regulating CXCL13. Supporting this contention, chemical sympathectomy significantly reduced expression of this chemokine. Together, we demonstrated that there does not appear to be a basis for synaptic neuro-immune communication, and that sympathetic innervation can modulate immune function through altering stromal cell chemokine production.

SUBMITTER: Murray K

PROVIDER: S-EPMC5533443 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Neuroanatomy of the spleen: Mapping the relationship between sympathetic neurons and lymphocytes.

Murray Kaitlin K Godinez Dayn Romero DR Brust-Mascher Ingrid I Miller Elaine Nicole EN Gareau Melanie G MG Reardon Colin C

PloS one 20170728 7

The nervous system plays a profound regulatory role in maintaining appropriate immune responses by signaling to immune cells. These immune cells, including B- and T-cells, can further act as intermediary messengers, with subsets of B- and T-cells expressing choline acetyltransferase (ChAT), the enzyme required for acetylcholine (ACh) synthesis. Neural control of ACh release from ChAT+ T-cells can have powerful immune implications, regulating lymphocyte trafficking, inflammation, and prevent deat ...[more]

PMID: 28753658

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Project description:Introduction: The cholinergic anti-inflammatory pathway (CAIP) has been proposed as an efferent neural pathway dampening the systemic inflammatory response via the spleen. The CAIP activates the splenic neural plexus and a subsequent series of intrasplenic events, which at least require a close association between sympathetic nerves and T cells. Knowledge on this pathway has mostly been derived from rodent studies and only scarce information is available on the innervation of the human spleen. This study aimed to investigate the sympathetic innervation of different structures of the human spleen, the topographical association of nerves with T cells and age-related variations in nerve distribution. Materials and Methods: Spleen samples were retrieved from a diagnostic archive and were allocated to three age groups; neonates, 10-25 and 25-70 years of age. Sympathetic nerves and T cells were identified by immunohistochemistry for tyrosine hydroxylase (TH) and the membrane marker CD3, respectively. The overall presence of sympathetic nerves and T cells was semi-automatically quantified and expressed as total area percentage. A predefined scoring system was used to analyze the distribution of nerves within different splenic structures. Results: Sympathetic nerves were observed in all spleens and their number appeared to slightly increase from birth to adulthood and to decrease afterward. Irrespective to age, more than halve of the periarteriolar lymphatic sheaths (PALSs) contained sympathetic nerves in close association with T cells. Furthermore, discrete sympathetic nerves were observed in the capsule, trabeculae and red pulp and comparable to the total amount of sympathetic nerves, showed a tendency to decrease with age. No correlation was found between the number of T cells and sympathetic nerves. Conclusion: The presence of discrete sympathetic nerves in the splenic parenchyma, capsule and trabecular of human spleens could suggest a role in functions other than vasoregulation. In the PALS, sympathetic nerves were observed to be in proximity to T cells and is suggestive for the existence of the CAIP in humans. Since sympathetic nerve distribution shows interspecies and age-related variation, and our general understanding of the relative and spatial contribution of splenic innervation in immune regulation is incomplete, it remains difficult to estimate the anti-inflammatory potential of targeting splenic nerves in patients.

Dataset Information

Neuroanatomy of the spleen: Mapping the relationship between sympathetic neurons and lymphocytes.

Publications

Neuroanatomy of the spleen: Mapping the relationship between sympathetic neurons and lymphocytes.

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