Distribution of nerve fibers and nerve-immune cell association in mouse spleen revealed by immunofluorescent staining

Abstract

The central nervous system regulates the immune system through the secretion of hormones from the pituitary gland and other endocrine organs, while the peripheral nervous system (PNS) communicates with the immune system through local nerve-immune cell interactions, including sympathetic/parasympathetic (efferent) and sensory (afferent) innervation to lymphoid tissue/organs. However, the precise mechanisms of this bi-directional crosstalk of the PNS and immune system remain mysterious. To study this kind of bi-directional crosstalk, we performed immunofluorescent staining of neurofilament and confocal microscopy to reveal the distribution of nerve fibers and nerveimmune cell associations inside mouse spleen. Our study demonstrates (i) extensive nerve fibers in all splenic compartments including the splenic nodules, periarteriolar lymphoid sheath, marginal zones, trabeculae, and red pulp; (ii) close associations of nerve fibers with blood vessels (including central arteries, marginal sinuses, penicillar arterioles, and splenic sinuses); (iii) close associations of nerve fibers with various subsets of dendritic cells, macrophages (Mac1 + and F4/80 +), and lymphocytes (B cells, T helper cells, and cytotoxic T cells). Our data concerning the extensive splenic innervation and nerve-immune cell communication will enrich our knowledge of the mechanisms through which the PNS affects the cellular-and humoral-mediated immune responses in healthy and infectious/noninfectious states. The human nervous system includes the central nervous system (CNS; containing the brain and spinal cord) and the peripheral nervous system (PNS; containing the sensory (somatic sensory and visceral sensory) and motor (somatic motor divisions and the autonomic nervous system (ANS; including sympathetic, parasympathetic, and enteric components))) 1. Recent studies have demonstrated that bi-directional communication/interaction between the nervous system and the immune system plays a crucial role in the host's responses to pathogen invasion, tissue injury, and other homeostatic dangers/threats 1-5. The functional organization of the neural control of the immune system is based on principles of reflex regulation 6. For example, the immune system is regulated by the CNS through the secretion of hormones from the pituitary and other neuroendocrine/endocrine organs 7,8 and by the PNS through local nerve (fiber)-immune cell interactions. The PNS can regulate the development, deployment, and homeostatic regulation of the immune system 3. This type of local neuroimmune interaction involves the "hardwiring" of sympathetic/parasympathetic (efferent) and visceral sensory (afferent) nerves to primary and secondary lymphoid tissue/organs 4-6. Neurotransmitters (e.g., acetylcholine, norepinephrine, and histamine) and neuropeptides (e.g., vasoactive intestinal peptide and substance P) released from nerve terminals (or even from the immune cells) might modulate the immune response in homeostasis and diseases 9. Cytokines and other immunologic factors synthesized a...

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