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Interactions between the Autonomic Nervous System and the Immune System after Stroke

Li Zhu, Leo Huang, Anh Le, Tom J. Wang, Jiewen Zhang, Xuemei Chen, Junmin Wang, Jian Wang, Chao Jiang

10.1002/cphy.c210047

Source: Volume 12, Issue 3, July 2022

Published online: June 2022

Full Article on Wiley Online Library



Abstract

Acute stroke is one of the leading causes of morbidity and mortality worldwide. Stroke‐induced immune‐inflammatory response occurs in the perilesion areas and the periphery. Although stroke‐induced immunosuppression may alleviate brain injury, it hinders brain repair as the immune‐inflammatory response plays a bidirectional role after acute stroke. Furthermore, suppression of the systemic immune‐inflammatory response increases the risk of life‐threatening systemic bacterial infections after acute stroke. Therefore, it is essential to explore the mechanisms that underlie the stroke‐induced immune‐inflammatory response. Autonomic nervous system (ANS) activation is critical for regulating the local and systemic immune‐inflammatory responses and may influence the prognosis of acute stroke. We review the changes in the sympathetic and parasympathetic nervous systems and their influence on the immune‐inflammatory response after stroke. Importantly, this article summarizes the mechanisms on how ANS regulates the immune‐inflammatory response through neurotransmitters and their receptors in immunocytes and immune organs after stroke. To facilitate translational research, we also discuss the promising therapeutic approaches modulating the activation of the ANS or the immune‐inflammatory response to promote neurologic recovery after stroke. © 2022 American Physiological Society. Compr Physiol 12:3665‐3704, 2022.

Figure 1. Figure 1. Autonomic innervation of the immune organs. The SNS preganglionic neurons are located in the lateral gray matter of the thoracic and lumbar spinal cord (Th1‐Th12 and L1‐L2). In contrast, the PNS preganglionic neurons, including the dorsal nucleus of the vagus nerve, are parasympathetic nuclei in the brainstem and lateral horn of the sacral cord (S2‐S4). The SNS postganglionic neurons are located in the sympathetic trunk, while the PNS postganglionic neurons are located in the organs' intramural ganglions that the postganglionic fibers innervate. The origin of postganglionic SNS fibers, which innervates the thymus, is currently known (the meaning of the first “?” symbol in this figure). The SNS fibers that innervate the spleen and liver originate from the celiac ganglion and superior mesenteric ganglion, while the postganglionic SNS fibers that innervate the intestine originate from superior mesenteric ganglion and inferior mesenteric ganglion. Whether the thymus receives PNS innervation is uncertain, whereas the spleen, liver, and intestine all receive vagus nerve innervation. In addition, the PNS from the lateral horn of S2 to S4 innervates the anus and rectum. The SNS may innervate the bone marrow of the femur from T8 to T12 and L1 and the PNS from parasympathetic neurons in the middle lateral column of the sacral spinal cord in mice, while knowledge about the SNS ganglion of postganglionic fibers that innervate the bone marrow is lacking (the meaning of the second “?” symbol in this figure). The preganglionic fibers of both the SNS and the PNS secrete ACh as the neurotransmitter. However, the SNS postganglionic fibers mainly secrete NE as the neurotransmitter, while postganglionic fibers of the PNS secrete ACh as the neurotransmitter. Abbreviations: ANS, autonomic nervous system; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; ACh, acetylcholine; NE, norepinephrine.
Figure 2. Figure 2. Changes in spleen‐related immune function modulated by ANS after stroke. Stroke induces SNS activation and alterations in PNS activation. Stroke also leads to spleen atrophy. α1‐ARs expressed in the splenic capsule may cause spleen contraction when NE activates it after acute stroke. SNS activation leads to changes in cellular and molecular immune constituents in the spleen, including an increase in splenocyte apoptosis, a decrease in T lymphocyte proliferation, an increase in Treg cell numbers, a decrease in CD69 expression, and IFN‐γ concentration through β‐ARs after acute stroke. Subsequently, these alterations in the spleen may lead to changes in the peripheral cellular and molecular immune components after acute stroke. SNS overactivation also resulted in B‐cell deficiency in the marginal zone of the spleen and decreased the circulating IgM levels after stroke. Cholinergic nerves also play an anti‐inflammatory role after stroke. PNS activation may inhibit macrophage activation and reduce proinflammatory cytokines, including TNF‐α, IFN‐γ, and IL‐6 in the spleen. Furthermore, increased NE release in the spleen may promote ACh release from splenic lymphocytes through β2‐ARs on the surface of splenic lymphocytes. However, research on the immune modulation of PNS in the spleen after acute stroke is scarce. Abbreviations: ANS, autonomic nervous system; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; ACh, acetylcholine; E, epinephrine; NE, norepinephrine; ARs, adrenergic receptors; nAChRs, nicotinic acetylcholine receptors; TNF, tumor necrosis factor; IFN, interferon; IL‐6, interleukin‐6.
Figure 3. Figure 3. Changes in intestine‐related immune function modulated by ANS after stroke. There is bidirectional communication between the CNS and the gut intestinal tract. Stroke can lead to microbiota dysbiosis, reduction in intestinal motility, disruption of the mucosal barrier, and intestinal immune dysfunction through cytokines released from the brain or by stimulation of the neurotransmitters of the ANS. On the contrary, microbiota dysbiosis and intestinal immune dysfunction can enhance the neuroinflammatory response and severity of brain injury and worsen the functional outcomes of stroke. Stroke may also induce commensal bacterial translocation and dissemination, increase commensal bacteria in the blood, and increase the incidence of infectious complications. In this double‐acting process, efferent SNS may promote, whereas efferent PNS may inhibit, mucosal barrier disruption, commensal bacterial translocation and dissemination, and intestinal immune dysfunction after acute stroke. However, as a negative feedback, microbiota metabolites such as LPS and SCFAs and intestinal GEC activation may inhibit the neuroinflammatory response and alleviate brain injury severity through activating the afferent PNS after stroke. Finally, acute stroke leads to increased adrenergic neurons and decreased cholinergic neurons in the intestine. Abbreviations: ANS, autonomic nervous system; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; BBB, blood‐brain barrier; LPS, lipopolysaccharide; SCFAs, short‐chain fatty acids; GEC, intestinal endocrine cell.
Figure 4. Figure 4. Changes in the function of immunocytes modulated by ANS after stroke. SNS overactivation induces B‐cell deficiency and increases the apoptosis of lymphocytes and NK cells through β2‐ARs. In contrast, it promotes the proliferation and migration of Treg cells through β2‐ARs and β3‐ARs, respectively, after stroke. Meanwhile, it inhibits the activation of iNKT cells and causes lymphocytes to shift from T helper (Th)1 to Th2 cytokine production after stroke. As for other immunocytes, α2‐AR or β2‐AR stimulation enhances BMDC endocytosis activity, inhibits the chemotactic response, reverses the increased IL12/IL23 ratio of LPS‐stimulated DCs, and decreases DC‐mediated Th1 cell differentiation in vitro. SNS overactivation promotes Treg cell proliferation and migration by regulating BMDC's function via β2‐ARs and β3‐ARs after stroke. However, overactivated SNS decreases neutrophil chemotaxis and phagocytosis, inhibits neutrophil activity and migration, promotes neutrophil differentiation toward the N2 phenotype, and decreases the expression of proinflammatory genes such as Fas, MyD88, and MMP9 after acute stroke. β2‐AR and α7‐nAChR stimulation on neutrophils, monocytes/macrophages, and microglia/astrocytes also alleviate the inflammatory response after acute stroke. All the above changes lead to immunosuppression in the early stage and an elevated risk of infection. ARs and AChRs are also present on the surfaces of mast cells. The impact of stimulation of the ANS on mast cells after stroke warrants exploration. Abbreviations: ANS, autonomic nervous system; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; NK cells, natural killer cells; iNKT cells, invariant natural killer T cells; Treg cells, regulatory T cells; DC, dendritic cells; BMDCs, bone marrow‐derived dendritic cells; CCL, chemokine C legend; NE, norepinephrine; ARs, adrenergic receptors; α7‐nAChRs, α7‐nicotinic acetylcholine receptors; MDMs, monocytes‐derived macrophages.
Figure 5. Figure 5. Changes in molecular immune system modulated by ANS after stroke. Through ANS, acute stroke induces a reduction in proinflammatory cytokines in peripheral blood, injured brain tissues, and organs, including the spleen, liver, heart, and intestine. Conversely, acute stroke also increases anti‐inflammatory cytokines in peripheral blood and the lesioned brain through the ANS. Abbreviations: ANS, autonomic nervous system; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; TNF, tumor necrosis factor; MCAO, middle cerebral artery occlusion; IFN, interferon; HMGB1, high‐mobility group box‐1 protein; TGF‐β, transforming growth factor‐β.
Figure 6. Figure 6. The potential mechanisms that underlie stroke‐associated infection complications are associated with the dysfunction of the ANS after stroke. Stroke induces a decrease in immune defense by reducing the immunocyte activity, promoting lymphocyte apoptosis, and reducing the ratio of pro‐/anti‐inflammatory cytokines in peripheral blood, immune organs, and lungs through the ANS and its neurotransmitters after acute stroke. Stroke also leads to an impaired immune response by inducing atrophy of immune organs, including the spleen and thymus, in the acute phase of stroke. Moreover, stroke‐induced ANS dysfunction may promote commensal bacterial translocation and dissemination, increase bacteria burden in blood and organs such as the lungs, and result in infectious complications after acute stroke. Abbreviations: ANS, autonomic nervous system; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; ACh, acetylcholine; E, epinephrine; NE, norepinephrine; Treg/Th17, the ratio of regulatory T cells to T‐helper 17 cells.


Figure 1. Autonomic innervation of the immune organs. The SNS preganglionic neurons are located in the lateral gray matter of the thoracic and lumbar spinal cord (Th1‐Th12 and L1‐L2). In contrast, the PNS preganglionic neurons, including the dorsal nucleus of the vagus nerve, are parasympathetic nuclei in the brainstem and lateral horn of the sacral cord (S2‐S4). The SNS postganglionic neurons are located in the sympathetic trunk, while the PNS postganglionic neurons are located in the organs' intramural ganglions that the postganglionic fibers innervate. The origin of postganglionic SNS fibers, which innervates the thymus, is currently known (the meaning of the first “?” symbol in this figure). The SNS fibers that innervate the spleen and liver originate from the celiac ganglion and superior mesenteric ganglion, while the postganglionic SNS fibers that innervate the intestine originate from superior mesenteric ganglion and inferior mesenteric ganglion. Whether the thymus receives PNS innervation is uncertain, whereas the spleen, liver, and intestine all receive vagus nerve innervation. In addition, the PNS from the lateral horn of S2 to S4 innervates the anus and rectum. The SNS may innervate the bone marrow of the femur from T8 to T12 and L1 and the PNS from parasympathetic neurons in the middle lateral column of the sacral spinal cord in mice, while knowledge about the SNS ganglion of postganglionic fibers that innervate the bone marrow is lacking (the meaning of the second “?” symbol in this figure). The preganglionic fibers of both the SNS and the PNS secrete ACh as the neurotransmitter. However, the SNS postganglionic fibers mainly secrete NE as the neurotransmitter, while postganglionic fibers of the PNS secrete ACh as the neurotransmitter. Abbreviations: ANS, autonomic nervous system; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; ACh, acetylcholine; NE, norepinephrine.


Figure 2. Changes in spleen‐related immune function modulated by ANS after stroke. Stroke induces SNS activation and alterations in PNS activation. Stroke also leads to spleen atrophy. α1‐ARs expressed in the splenic capsule may cause spleen contraction when NE activates it after acute stroke. SNS activation leads to changes in cellular and molecular immune constituents in the spleen, including an increase in splenocyte apoptosis, a decrease in T lymphocyte proliferation, an increase in Treg cell numbers, a decrease in CD69 expression, and IFN‐γ concentration through β‐ARs after acute stroke. Subsequently, these alterations in the spleen may lead to changes in the peripheral cellular and molecular immune components after acute stroke. SNS overactivation also resulted in B‐cell deficiency in the marginal zone of the spleen and decreased the circulating IgM levels after stroke. Cholinergic nerves also play an anti‐inflammatory role after stroke. PNS activation may inhibit macrophage activation and reduce proinflammatory cytokines, including TNF‐α, IFN‐γ, and IL‐6 in the spleen. Furthermore, increased NE release in the spleen may promote ACh release from splenic lymphocytes through β2‐ARs on the surface of splenic lymphocytes. However, research on the immune modulation of PNS in the spleen after acute stroke is scarce. Abbreviations: ANS, autonomic nervous system; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; ACh, acetylcholine; E, epinephrine; NE, norepinephrine; ARs, adrenergic receptors; nAChRs, nicotinic acetylcholine receptors; TNF, tumor necrosis factor; IFN, interferon; IL‐6, interleukin‐6.


Figure 3. Changes in intestine‐related immune function modulated by ANS after stroke. There is bidirectional communication between the CNS and the gut intestinal tract. Stroke can lead to microbiota dysbiosis, reduction in intestinal motility, disruption of the mucosal barrier, and intestinal immune dysfunction through cytokines released from the brain or by stimulation of the neurotransmitters of the ANS. On the contrary, microbiota dysbiosis and intestinal immune dysfunction can enhance the neuroinflammatory response and severity of brain injury and worsen the functional outcomes of stroke. Stroke may also induce commensal bacterial translocation and dissemination, increase commensal bacteria in the blood, and increase the incidence of infectious complications. In this double‐acting process, efferent SNS may promote, whereas efferent PNS may inhibit, mucosal barrier disruption, commensal bacterial translocation and dissemination, and intestinal immune dysfunction after acute stroke. However, as a negative feedback, microbiota metabolites such as LPS and SCFAs and intestinal GEC activation may inhibit the neuroinflammatory response and alleviate brain injury severity through activating the afferent PNS after stroke. Finally, acute stroke leads to increased adrenergic neurons and decreased cholinergic neurons in the intestine. Abbreviations: ANS, autonomic nervous system; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; BBB, blood‐brain barrier; LPS, lipopolysaccharide; SCFAs, short‐chain fatty acids; GEC, intestinal endocrine cell.


Figure 4. Changes in the function of immunocytes modulated by ANS after stroke. SNS overactivation induces B‐cell deficiency and increases the apoptosis of lymphocytes and NK cells through β2‐ARs. In contrast, it promotes the proliferation and migration of Treg cells through β2‐ARs and β3‐ARs, respectively, after stroke. Meanwhile, it inhibits the activation of iNKT cells and causes lymphocytes to shift from T helper (Th)1 to Th2 cytokine production after stroke. As for other immunocytes, α2‐AR or β2‐AR stimulation enhances BMDC endocytosis activity, inhibits the chemotactic response, reverses the increased IL12/IL23 ratio of LPS‐stimulated DCs, and decreases DC‐mediated Th1 cell differentiation in vitro. SNS overactivation promotes Treg cell proliferation and migration by regulating BMDC's function via β2‐ARs and β3‐ARs after stroke. However, overactivated SNS decreases neutrophil chemotaxis and phagocytosis, inhibits neutrophil activity and migration, promotes neutrophil differentiation toward the N2 phenotype, and decreases the expression of proinflammatory genes such as Fas, MyD88, and MMP9 after acute stroke. β2‐AR and α7‐nAChR stimulation on neutrophils, monocytes/macrophages, and microglia/astrocytes also alleviate the inflammatory response after acute stroke. All the above changes lead to immunosuppression in the early stage and an elevated risk of infection. ARs and AChRs are also present on the surfaces of mast cells. The impact of stimulation of the ANS on mast cells after stroke warrants exploration. Abbreviations: ANS, autonomic nervous system; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; NK cells, natural killer cells; iNKT cells, invariant natural killer T cells; Treg cells, regulatory T cells; DC, dendritic cells; BMDCs, bone marrow‐derived dendritic cells; CCL, chemokine C legend; NE, norepinephrine; ARs, adrenergic receptors; α7‐nAChRs, α7‐nicotinic acetylcholine receptors; MDMs, monocytes‐derived macrophages.


Figure 5. Changes in molecular immune system modulated by ANS after stroke. Through ANS, acute stroke induces a reduction in proinflammatory cytokines in peripheral blood, injured brain tissues, and organs, including the spleen, liver, heart, and intestine. Conversely, acute stroke also increases anti‐inflammatory cytokines in peripheral blood and the lesioned brain through the ANS. Abbreviations: ANS, autonomic nervous system; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; TNF, tumor necrosis factor; MCAO, middle cerebral artery occlusion; IFN, interferon; HMGB1, high‐mobility group box‐1 protein; TGF‐β, transforming growth factor‐β.


Figure 6. The potential mechanisms that underlie stroke‐associated infection complications are associated with the dysfunction of the ANS after stroke. Stroke induces a decrease in immune defense by reducing the immunocyte activity, promoting lymphocyte apoptosis, and reducing the ratio of pro‐/anti‐inflammatory cytokines in peripheral blood, immune organs, and lungs through the ANS and its neurotransmitters after acute stroke. Stroke also leads to an impaired immune response by inducing atrophy of immune organs, including the spleen and thymus, in the acute phase of stroke. Moreover, stroke‐induced ANS dysfunction may promote commensal bacterial translocation and dissemination, increase bacteria burden in blood and organs such as the lungs, and result in infectious complications after acute stroke. Abbreviations: ANS, autonomic nervous system; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; ACh, acetylcholine; E, epinephrine; NE, norepinephrine; Treg/Th17, the ratio of regulatory T cells to T‐helper 17 cells.
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Article Title: Interactions between the Autonomic Nervous System and the Immune System after Stroke
 

How to Cite

Li Zhu, Leo Huang, Anh Le, Tom J. Wang, Jiewen Zhang, Xuemei Chen, Junmin Wang, Jian Wang, Chao Jiang. Interactions between the Autonomic Nervous System and the Immune System after Stroke. Compr Physiol 2022, 12: 3665-3704. doi: 10.1002/cphy.c210047