Age-Related Variation in Sympathetic Nerve Distribution in the Human Spleen

Abstract

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.

Sympathetic innervation of human and porcine spleens: implications for between species variation in function

“…This is important because the current model of the CAP, which was developed largely in rodent models, envisions a close association of sympathetic nerves with cholinergic T cells in the white pulp. Previous research performed with human tissue found that noradrenergic innervation of human spleen is mainly localized to the arterial vasculature and very sparse in the white pulp compared to that of rodent spleens (Cleypool et al, 2021 , Hoover et al, 2017 , Verlinden et al, 2019 ). Our findings support this view of sparse innervation of splenic parenchyma by using donor tissue immediately fixed while still viable and treated with two different antigen retrieval protocols.…”

“…Several previous immunohistochemical studies evaluated sympathetic innervation of human spleen, using primarily archived autopsy samples and a limited number of fresh frozen samples (Cleypool et al, 2021 , Hoover et al, 2017 , Verlinden et al, 2019 ). This work was consistent in finding that a vast majority of noradrenergic nerves in the human spleen occurred around the arterial vasculature, where they were localized to perivascular adventitia.…”

“…​ Several recent studies including ours have specifically evaluated noradrenergic innervation of the human spleen (Cleypool et al, 2021 , Hoover et al, 2017 , Verlinden et al, 2019 ), and all identified innervation of splenic arteries down to the level of central arteries and arterioles, which are surrounded by white pulp. Two of these studies reported a few noradrenergic nerve fibers making short excursions into surrounding white pulp (Cleypool et al, 2021 , Hoover et al, 2017 ), and one reported that some noradrenergic fibers occurred near CD3 + T cells (Cleypool et al, 2021 ). However, none of them observed dense sympathetic innervation of the white pulp as reported for mice and rats.…”

Immune, endothelial and neuronal network map in human lymph node and spleen

“…However, much of our knowledge regarding the architecture and function of the lymphatic system derives from rodents 11 , with recent studies noting a series of key architectural differences compared to humans [12][13][14] . Indeed, recent 3D imaging and topological mapping of the murine LN 15,16 have described a mesh-like network composed of fibroblastic reticular cells (FRCs) that provide the homing zone for T cells and may mediate B cell homeostasis 17 .…”

“…The autonomic nervous system provides control of host immune defense mechanisms through innervation from sympathetic postganglionic neurons, specifically the splenic nerve for the SPL and anatomically paired nerve fibers for respective LNs 10 . However, much of our knowledge regarding the architecture and function of the lymphatic system derives from rodents 11 , with recent studies noting a series of key architectural differences compared to humans 12–14 .…”