Acute spinal cord injury (SCI) causes systemic immunosuppression and life-threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus–pituitary–adrenal axis stimulation. Instead of consecutive hypothalamus–pituitary–adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism. This neurogenic effect was more pronounced after high-thoracic level (Th1) SCI disconnecting adrenal gland innervation, compared with low-thoracic level (Th9) SCI. Prophylactic adrenalectomy completely prevented SCI-induced glucocorticoid excess and lymphocyte depletion but did not prevent pneumonia. When adrenalectomized mice were transplanted with denervated adrenal glands to restore physiologic glucocorticoid levels, the animals were completely protected from pneumonia. These findings identify a maladaptive sympathetic-neuroendocrine adrenal reflex mediating immunosuppression after SCI, implying that therapeutic normalization of the glucocorticoid and catecholamine imbalance in SCI patients could be a strategy to prevent detrimental infections.
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Steinman, L. Elaborate interactions between the immune and nervous systems. Nat. Immunol. 5, 575–581 (2004).
Irwin, M.R. & Cole, S.W. Reciprocal regulation of the neural and innate immune systems. Nat. Rev. Immunol. 11, 625–632 (2011).
Meisel, C., Schwab, J.M., Prass, K., Meisel, A. & Dirnagl, U. Central nervous system injury-induced immune deficiency syndrome. Nat. Rev. Neurosci. 6, 775–786 (2005).
Lucin, K.M., Sanders, V.M. & Popovich, P.G. Stress hormones collaborate to induce lymphocyte apoptosis after high level spinal cord injury. J. Neurochem. 110, 1409–1421 (2009).
Riegger, T. et al. Spinal cord injury-induced immune depression syndrome (SCI-IDS). Eur. J. Neurosci. 25, 1743–1747 (2007).
Oropallo, M.A. et al. Chronic spinal cord injury impairs primary antibody responses but spares existing humoral immunity in mice. J. Immunol. 188, 5257–5266 (2012).
Riegger, T. et al. Immune depression syndrome following human spinal cord injury (SCI): a pilot study. Neuroscience 158, 1194–1199 (2009).
Furlan, J.C., Krassioukov, A.V. & Fehlings, M.G. Hematologic abnormalities within the first week after acute isolated traumatic cervical spinal cord injury: a case-control cohort study. Spine 31, 2674–2683 (2006).
Brommer, B. et al. Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level. Brain 139, 692–707 (2016).
DeVivo, M.J., Kartus, P.L., Stover, S.L., Rutt, R.D. & Fine, P.R. Cause of death for patients with spinal cord injuries. Arch. Intern. Med. 149, 1761–1766 (1989).
Jackson, A.B. & Groomes, T.E. Incidence of respiratory complications following spinal cord injury. Arch. Phys. Med. Rehabil. 75, 270–275 (1994).
Failli, V. et al. Functional neurological recovery after spinal cord injury is impaired in patients with infections. Brain 135, 3238–3250 (2012).
Kopp, M.A. et al. Long-term functional outcome in patients with acquired infections after acute spinal cord injury. Neurology 88, 892–900 (2017).
Borovikova, L.V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000).
Martelli, D., Yao, S.T., McKinley, M.J. & McAllen, R.M. Reflex control of inflammation by sympathetic nerves, not the vagus. J. Physiol. (Lond.) 592, 1677–1686 (2014).
Zhang, Y. et al. Autonomic dysreflexia causes chronic immune suppression after spinal cord injury. J. Neurosci. 33, 12970–12981 (2013).
Ueno, M., Ueno-Nakamura, Y., Niehaus, J., Popovich, P.G. & Yoshida, Y. Silencing spinal interneurons inhibits immune suppressive autonomic reflexes caused by spinal cord injury. Nat. Neurosci. 19, 784–787 (2016).
Meador, K.J. et al. Role of cerebral lateralization in control of immune processes in humans. Ann. Neurol. 55, 840–844 (2004).
Walter, U. et al. Insular stroke is associated with acute sympathetic hyperactivation and immunodepression. Eur. J. Neurol. 20, 153–159 (2013).
Williams, J.M. et al. Sympathetic innervation of murine thymus and spleen: evidence for a functional link between the nervous and immune systems. Brain Res. Bull. 6, 83–94 (1981).
Felten, D.L., Ackerman, K.D., Wiegand, S.J. & Felten, S.Y. Noradrenergic sympathetic innervation of the spleen: I. Nerve fibers associate with lymphocytes and macrophages in specific compartments of the splenic white pulp. J. Neurosci. Res. 18, 28–36, 118–121 (1987).
Previnaire, J.G., Soler, J.M., El Masri, W. & Denys, P. Assessment of the sympathetic level of lesion in patients with spinal cord injury. Spinal Cord 47, 122–127 (2009).
Wong, C.H., Jenne, C.N., Lee, W.Y., Léger, C. & Kubes, P. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science 334, 101–105 (2011).
Massberg, S. et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 131, 994–1008 (2007).
Dembowsky, K., Czachurski, J., Amendt, K. & Seller, H. Tonic descending inhibition of the spinal somato-sympathetic reflex from the lower brain stem. J. Auton. Nerv. Syst. 2, 157–182 (1980).
Tibbs, P.A., Young, B., McAllister, R.G. Jr. & Todd, E.P. Studies of experimental cervical spinal cord transection. Part III: Effects of acute cervical spinal cord transection on cerebral blood flow. J. Neurosurg. 50, 633–638 (1979).
Rawe, S.E. & Perot, P.L. Jr. Pressor response resulting from experimental contusion injury to the spinal cord. J. Neurosurg. 50, 58–63 (1979).
Young, W., DeCrescito, V., Tomasula, J.J. & Ho, V. The role of the sympathetic nervous system in pressor responses induced by spinal injury. J. Neurosurg. 52, 473–481 (1980).
Edwards, A.V. & Jones, C.T. Autonomic control of adrenal function. J. Anat. 183, 291–307 (1993).
Parker, T.L., Kesse, W.K., Mohamed, A.A. & Afework, M. The innervation of the mammalian adrenal gland. J. Anat. 183, 265–276 (1993).
Holzwarth, M.A., Cunningham, L.A. & Kleitman, N. The role of adrenal nerves in the regulation of adrenocortical functions. Ann. NY Acad. Sci. 512, 449–464 (1987).
Dhabhar, F.S. & McEwen, B.S. Enhancing versus suppressive effects of stress hormones on skin immune function. Proc. Natl. Acad. Sci. USA 96, 1059–1064 (1999).
Andersson, U. & Tracey, K.J. Neural reflexes in inflammation and immunity. J. Exp. Med. 209, 1057–1068 (2012).
Dimitrov, S. et al. Cortisol and epinephrine control opposing circadian rhythms in T cell subsets. Blood 113, 5134–5143 (2009).
Scheiermann, C. et al. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity 37, 290–301 (2012).
Schedlowski, M. et al. Catecholamines modulate human NK cell circulation and function via spleen-independent beta 2-adrenergic mechanisms. J. Immunol. 156, 93–99 (1996).
Prass, K. et al. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J. Exp. Med. 198, 725–736 (2003).
Lucin, K.M., Sanders, V.M., Jones, T.B., Malarkey, W.B. & Popovich, P.G. Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation. Exp. Neurol. 207, 75–84 (2007).
Rouleau, P., Ung, R.V., Lapointe, N.P. & Guertin, P.A. Hormonal and immunological changes in mice after spinal cord injury. J. Neurotrauma 24, 367–378 (2007).
von Andrian, U.H. Intravital microscopy of the peripheral lymph node microcirculation in mice. Microcirculation 3, 287–300 (1996).
Kopp, M.A. et al. The SCIentinel study--prospective multicenter study to define the spinal cord injury-induced immune depression syndrome (SCI-IDS)--study protocol and interim feasibility data. BMC Neurol. 13, 168 (2013).
Fatima, G., Sharma, V.P. & Verma, N.S. Circadian variations in melatonin and cortisol in patients with cervical spinal cord injury. Spinal Cord 54, 364–367 (2016).
We thank P. Popovich for critically reading the manuscript and insightful suggestions. We are grateful for the excellent technical help of D. Brandl, L. Mosch, C. Josties and I. Przesdzing. This work has been supported by grants from the German Academic Exchange Service (DAAD, D/10/43923) and German Research Foundation (DFG, PR 1274/2-1 to H.P.; STU 528/1-1, CRC-914 to S.S. and Cluster of Excellence NeuroCure to U.D.), by the Wings for Life Spinal Cord Research Foundation (WfL-DE-006/12), Else Kröner Fresenius Stiftung, German legal accident insurance (DGUV), the Era-Net-NEURON Program of the European Union, NIDILRR (#90SI5020), the Ohio State University Discovery Theme and the W.E. Hunt & C.M. Curtis Endowment to J.M.S. The National Spinal Cord Injury Database (NSCID) is funded by the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR, Grant number 90DP0083), US Department of Health and Human Services. This work was supported by the HMS Center for Immune Imaging and NIH grants AI112521 and AR068383 (to U.H.v.A.).
The authors declare no competing financial interests.
Integrated supplementary information
The SCI-induced reduction in organ size was detectable already after 24 hours (a) and progresses continuously to 48 hours (b). Already at these early time points, cell loss is related to the level of SCI. Data are mean ± SEM, n=3 animals per group. * p<0.05; ** p<0.01; 1-way ANOVA with Tukey’s multiple comparison test.
FACS gating strategy exemplarily shown for CD19+ B cells (a, leukocytes; b, single cells; c, CD19+ cells). The profound cell loss affected all major immune cell populations including CD19+ B cells (d), CD4+ T cells (e), CD8+ T cells (f), CD11c+ dendritic cells (g), CD11b+ monocytes (h), and NK1.1+ NK cells (i). Data are mean ± SEM, n=3-5 animals per group. * p<0.05; ** p<0.01; *** p<0.001, 1-way ANOVA with Tukey’s multiple comparison test.
Supplementary Figure 3 Sciatic nerve lesion has no effect on immune cell composition of the innervated bone marrow.
(a) Deafferentiation of the tibial bone marrow by right sciatic nerve injury (compared to sham) did not change the total number of bone marrow cells. (b-d) Right sciatic nerve lesion did not change the number and frequency of CD19+ (b), CD4+ (c), CD8+ (d), Gr-1+, NK1.1+, CD11c+, and CD11b+ cells (not shown) in the ipsi- and contralateral bone marrow. (e-f) Homing of donor splenocytes for 2 hours (e) as well as redistribution for 15 hours (f) to the bone marrow was equal in mice with right sciatic nerve lesion and sham-operated animals. Data are mean ± SEM, n=6-9 animals per group. * p<0.05; 1-way ANOVA with Tukey’s multiple comparison test.
Supplementary Figure 4 Adrenalectomy reversed the SCI-induced cell depletion in all analyzed types of immune cells.
Adrenalectomy prevented the loss of all examined cell populations 72 hours after SCI. In particular, the number of CD19+ (a), CD4+ (b), CD8+ (c), CD11c+ and CD11b+ cells (not shown) were unchanged after SCI. Data are mean ± SEM, n=3 animals per group. * p<0.05; ** p<0.01; *** p<0.001, 1-way ANOVA with Tukey’s multiple comparison test.
In contrast to surgical removal of the adrenals, removal of the spleen which is similarly innervated by sympathetic fibers via the splanchnic nerve, could not re-establish the SCI-induced cell death in thymus and lymph nodes (a) and did not change the characteristic SCI-induced pattern of B cell populations in the bone marrow (b-e) with massive enrichment of mature B cells (e).
Supplementary Figure 6 Adrenotransplantation reduced effects of lesion height and protected from pneumonia after SCI.
Disconnection of the adrenal glands from spinal innervation (adrenotransplantation) resulted in only subtle differences in organ shrinkage between high versus low thoracic level SCI (Th1/Th9). This held true for all examined cell populations, including CD4+ (a), CD19+ (b), CD8+ (c), CD11c+, and CD11b+ cells (not shown). Data are mean ± SEM, n=3-7 animals per group. * p<0.05; ** p<0.01; *** p<0.001, 1-way ANOVA with Tukey’s multiple comparison test.
Numbers and percentages of liver iNKT cells were not altered after experimental SCI in wild-type mice after adrenalectomy (a) and adrenotransplantation (b). Data are mean ± SEM, n=3-4 animals per group. * p<0.05; 1-way ANOVA with Tukey’s multiple comparison test.
Homing of injected donor splenocytes (composed of ~52% CD19+, ~23% CD4+, ~17% CD8+ cells) was not equally impaired for all donor cell populations or target organs. (a) The homing deficit was most pronounced for B cells with reduced percentage of CD19+ cells (only 30% B cells after SCI compared to almost 60% after sham), while the percentage of T cells in the donor population was increased (despite total reduction). (b) In contrast, homing of donor cells to the cervical LNs was equally impaired for all cell populations after SCI. (c) The 2-hour homing deficit of donor cells to most organs was detectable already 1 d post SCI, most pronounced to peripheral LNs. (d) Not only homing, but also redistribution of donor cells (15 hours cell migration) was severely disturbed after SCI. Data are mean ± SEM, n=3-5 (a-b) or 3 (c-d) animals per group. * p<0.05; ** p<0.01; *** p<0.001, unpaired Student’s t test (a-b) or 1-way ANOVA with Tukey’s multiple comparison test (c-d).
(a) In vivo imaging of the inguinal LN showed that rolling of T lymphocytes after SCI was not impaired. (b) In the shrunken brachial LN after SCI, the expression level of PNAd (MECA-79 antibody) appeared increased. (c) In contrast to spleen and LNs, homing to the bone marrow is only slightly changed with a subtle increase of CD4+ and CD8+ T cells. (d) BM mRNA expression of CXCL12 was increased. (e) BM of injured mice (3d post SCI) recruits ~5 times more mature B cells from the circulation 24 hours after injection. Homing to BM is completely abolished if B cells were pre-treated with pertussis toxin in vitro. Data are mean ± SEM, n=3-5 animals per group. * p<0.05; ** p<0.01; *** p<0.001, unpaired Student’s t test. Bar represents 1 mm in b.
Supplementary Figure 10 Cascade of events showing how SCI ultimately results in neuroendocrine dysfunction involving the adrenal glands and leading to infection.
(a) High-level (Th1) SCI interrupts neural vegetative innervation of the adrenal glands from the spinal cord via splanchnic and adrenal nerves. (b) Adrenal denervation results in a drop of CA release and in disinhibition of GC release. Increased GCs then suppress ACTH production (primary hypercortisolism). Dysfunctional neuro-endocrine signaling leads to high GC and low NE levels which promote infections via pathways including reduced cardiac output, disturbed lymphocyte trafficking, or increased immune cell apoptosis. (c) The susceptibility to pneumonia was reversed if GC levels remained balanced in adrenotransplanted animals. The figure additionally shows how further pathways of immune dysfunction after SCI interfere with the here presented cascade. For example, vagus nerve-mediated parasympathetic innervation of the cardiovascular system (top) or spleen and liver (bottom) intersect with the sympathetic route. This might be of particular relevance to lesions of the central nervous system, which are located above the originating vagus fibers in the brainstem, such as in stroke.
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Prüss, H., Tedeschi, A., Thiriot, A. et al. Spinal cord injury-induced immunodeficiency is mediated by a sympathetic-neuroendocrine adrenal reflex. Nat Neurosci 20, 1549–1559 (2017). https://doi.org/10.1038/nn.4643
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