The
n e w e ng l a n d j o u r na l
of
m e dic i n e
clinical implications of basic research Elizabeth G. Phimister, Ph.D., Editor
Bacteria and the Neural Code Benjamin E. Steinberg, M.D., Ph.D., Kevin J. Tracey, M.D., and Arthur S. Slutsky, M.D. The current approach for the definitive diagnosis of infection requires the analysis of body fluids or tissues, often acquired through invasive procedures. The results of these tests may take hours, days, or even longer to obtain. Yet timely diagnosis and intervention are essential to minimize patient morbidity and mortality. For example, for a patient in septic shock, prompt administration of antibiotic agents is imperative, since each hour of delay is associated with an increase in mortality of 7.6 percentage points.1 Studies showing that the nervous system senses and responds to infectious and sterile inflammation suggest that its activity may be more informative than is generally perceived. In experiments in mice, Chiu et al.2 observed that substances produced by Staphylococcus aureus, such as formylated peptides and the α-hemo lysin toxin, directly activated a group of sensory neurons that includes nociceptors. Neuronal activation occurred through direct interactions between the bacterial products and the neuronal membrane proteins Fpr1 and Adam10. This sensing mechanism bypassed the innate immune system; moreover, when these sensory neurons were ablated, infection with the pathogen resulted in greater immune infiltration and lymphadenopathy due to decreased release of immune-modulating neuropeptides.2 Thus, neural signals, propagated through axon–axon reflexes, culminate in the local release of CGRP, galanin, and somatostatin at the site of infection (Fig. 1A). The engagement of neural receptors by cognate ligands in turn regulates the activity of infiltrating immune cells, limiting inflammation and damage. More recent work by an independent set of investigators, Riol-Blanco et al.,3 showed that a subset of neurons in mice modulates the cutaneous inflammatory response in dermal psoriatic inflammation by regulating cytokine responses from inflammation-inducing dermal
dendritic cells (Fig. 1B). Pharmacologic denervation of nociceptive sensory neurons in psoriasi form inflammation induced by topical imiquimod decreased local swelling and inflammation. (This effect was independent of T-cell priming in or recruitment from skin-draining lymph nodes, which further suggested that there was direct neuronal control of cutaneous inflammation.) These same neurons terminate on resident dendritic cells that generate interleukin-23, which drives a cytokine cascade and ultimately drives psoriasiform skin inflammation. The nature of the interaction between the neurons and dendritic cells remains unclear and should be the focus of future investigation. Together, these studies indicate that sensory neurons can integrate information about the local infectious and inflammatory environment to reflexively modulate immune responses. Autonomic neurons have also been implicated in the regulation of inflammation.4 For example, in seminal work by Watkins et al.,5 subdiaphragmatic vagotomy prevented pyrexia in mice receiving systemic interleukin-1β. Autonomic reflex circuits, therefore, perceive immune and inflammatory signals within the viscera. Whether the inflammatory mediators directly activate these neurons — as seems to be the case with nociceptive sensory neurons — or whether intermediate steps lead to autonomic neuronal activation is an area of active research. Notably, as the inciting infection initiates immune and physiological responses, those changes are monitored in real time by peripheral sensory neural networks. It follows that an ensemble of information related to physiological, metabolic, and immunologic reactions is available to the nervous system, which mobilizes antimicrobial processes, at least in some contexts. The density of the sensory neural net ensures that virtually all of the cells in the body can interact electrically and communicate afferent infor-
n engl j med 371;22 nejm.org november 27, 2014
2131
The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on November 27, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
The
n e w e ng l a n d j o u r na l
A
of
m e dic i n e
B α-Hemolysin toxin
Formylated peptide
Dormant dendritic cells
Imiquimod
FPR1
Neural response
ADAM10
Axon cytoplasm Ca
2+
Propagation of action potential
Activated dendritic cells
Axon–axon reflex Interleukin-23 Neuropeptide release
γδ T cells Infiltrating immune cells TRPV1+ Nav1.8+ nociceptor
Nav1.8+ nociceptor
Interleukin-17
Interleukin-22
To the CNS Neuropeptides bind to immune-cell receptors
Psoriasiform skin inflammation
Modulated immune responses
γδ T cell
Neutrophil
mation to the brain about the immune status of cific to a given pathogen as well as to the host the body. It is possible that the neural signa- response — that is, the nervous system may be tures encoded in these electrical signals are spe- able to discriminate not only the location of an 2132
n engl j med 371;22
nejm.org
november 27, 2014
The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on November 27, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
clinical implications of basic research
Figure 1 (facing page). Neuronal Sensing and Modulation of the Local Immune Environment. Subsets of sensory neurons can integrate information about the local infectious and inflammatory environment to modulate immune responses.2,3 Panel A is adapted from Chiu et al.2 Formylated peptides and α-hemolysin toxin from Staphylococcus aureus activate Nav1.8+ nociceptors through FPR1 and ADAM10, respectively. Neuronal activation leads to an axon–axon reflex (dashed black line) that results in signals propagating to nerve terminals and to the release of neuropeptides such as CGRP, galanin, and somatostatin. These mediators bind their receptors on infiltrating immune cells and modify the local inflammatory response. Panel B is adapted from Riol-Blanco et al.3 TRPV1+ Nav1.8+ nociceptors drive psoriasiform skin inflammation induced by topical imiquimod. These peripheral sensory nerves are in close proximity to interleukin-23–producing dermal dendritic cells. The interleukin-23 activates γδ T cells, which release interleukin-22 and interleukin-17; this culminates in skin inflammation and keratinocyte activation and proliferation. CNS denotes central nervous system.
infection but also the type of pathogen causing it. We hypothesize that capturing and decoding this information through nerve recordings will permit diagnosis and monitoring of the course of an infectious disease. Testing this hypothesis will require the expansion of domains in both medicine and engineering. Once available, a compendium of microbiologic electrical signatures might be extended to therapeutics, to provide personalized antibiotic, immune-modulating therapies or perhaps
even therapies delivered by replication of these signatures. As demonstrated by Chiu et al. and Riol-Blanco et al., the functional capacity of the sensory neurons themselves extends beyond simply reporting on environmental challenges and includes active immune-regulating effects. In principle, by combining the reading and writing of neural information, it may be possible to establish closed-loop systems that modulate inflammatory or immune responses to improve patient outcomes. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the Department of Anesthesia, University of Toronto (B.E.S.), and the Keenan Research Centre for Biomedical Science, St. Michael’s Hospital (A.S.S.) — both in Toronto; and the Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, NY (K.J.T.). 1. Kumar A, Roberts D, Wood KE, et al. Duration of hypoten-
sion before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006;34:1589-96. 2. Chiu IM, Heesters BA, Ghasemlou N, et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 2013;501:52-7. 3. Riol-Blanco L, Ordovas-Montanes J, Perro M, et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 2014;510:157-61. 4. Andersson U, Tracey KJ. Reflex principles of immunological homeostasis. Annu Rev Immunol 2012;30:313-35. 5. Watkins LR, Goehler LE, Relton JK, et al. Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication. Neurosci Lett 1995;183:27-31. DOI: 10.1056/NEJMcibr1412003 Copyright © 2014 Massachusetts Medical Society.
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n engl j med 371;22 nejm.org november 27, 2014
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The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on November 27, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
n e w e ng l a n d j o u r na l
of
m e dic i n e
clinical implications of basic research Elizabeth G. Phimister, Ph.D., Editor
Bacteria and the Neural Code Benjamin E. Steinberg, M.D., Ph.D., Kevin J. Tracey, M.D., and Arthur S. Slutsky, M.D. The current approach for the definitive diagnosis of infection requires the analysis of body fluids or tissues, often acquired through invasive procedures. The results of these tests may take hours, days, or even longer to obtain. Yet timely diagnosis and intervention are essential to minimize patient morbidity and mortality. For example, for a patient in septic shock, prompt administration of antibiotic agents is imperative, since each hour of delay is associated with an increase in mortality of 7.6 percentage points.1 Studies showing that the nervous system senses and responds to infectious and sterile inflammation suggest that its activity may be more informative than is generally perceived. In experiments in mice, Chiu et al.2 observed that substances produced by Staphylococcus aureus, such as formylated peptides and the α-hemo lysin toxin, directly activated a group of sensory neurons that includes nociceptors. Neuronal activation occurred through direct interactions between the bacterial products and the neuronal membrane proteins Fpr1 and Adam10. This sensing mechanism bypassed the innate immune system; moreover, when these sensory neurons were ablated, infection with the pathogen resulted in greater immune infiltration and lymphadenopathy due to decreased release of immune-modulating neuropeptides.2 Thus, neural signals, propagated through axon–axon reflexes, culminate in the local release of CGRP, galanin, and somatostatin at the site of infection (Fig. 1A). The engagement of neural receptors by cognate ligands in turn regulates the activity of infiltrating immune cells, limiting inflammation and damage. More recent work by an independent set of investigators, Riol-Blanco et al.,3 showed that a subset of neurons in mice modulates the cutaneous inflammatory response in dermal psoriatic inflammation by regulating cytokine responses from inflammation-inducing dermal
dendritic cells (Fig. 1B). Pharmacologic denervation of nociceptive sensory neurons in psoriasi form inflammation induced by topical imiquimod decreased local swelling and inflammation. (This effect was independent of T-cell priming in or recruitment from skin-draining lymph nodes, which further suggested that there was direct neuronal control of cutaneous inflammation.) These same neurons terminate on resident dendritic cells that generate interleukin-23, which drives a cytokine cascade and ultimately drives psoriasiform skin inflammation. The nature of the interaction between the neurons and dendritic cells remains unclear and should be the focus of future investigation. Together, these studies indicate that sensory neurons can integrate information about the local infectious and inflammatory environment to reflexively modulate immune responses. Autonomic neurons have also been implicated in the regulation of inflammation.4 For example, in seminal work by Watkins et al.,5 subdiaphragmatic vagotomy prevented pyrexia in mice receiving systemic interleukin-1β. Autonomic reflex circuits, therefore, perceive immune and inflammatory signals within the viscera. Whether the inflammatory mediators directly activate these neurons — as seems to be the case with nociceptive sensory neurons — or whether intermediate steps lead to autonomic neuronal activation is an area of active research. Notably, as the inciting infection initiates immune and physiological responses, those changes are monitored in real time by peripheral sensory neural networks. It follows that an ensemble of information related to physiological, metabolic, and immunologic reactions is available to the nervous system, which mobilizes antimicrobial processes, at least in some contexts. The density of the sensory neural net ensures that virtually all of the cells in the body can interact electrically and communicate afferent infor-
n engl j med 371;22 nejm.org november 27, 2014
2131
The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on November 27, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
The
n e w e ng l a n d j o u r na l
A
of
m e dic i n e
B α-Hemolysin toxin
Formylated peptide
Dormant dendritic cells
Imiquimod
FPR1
Neural response
ADAM10
Axon cytoplasm Ca
2+
Propagation of action potential
Activated dendritic cells
Axon–axon reflex Interleukin-23 Neuropeptide release
γδ T cells Infiltrating immune cells TRPV1+ Nav1.8+ nociceptor
Nav1.8+ nociceptor
Interleukin-17
Interleukin-22
To the CNS Neuropeptides bind to immune-cell receptors
Psoriasiform skin inflammation
Modulated immune responses
γδ T cell
Neutrophil
mation to the brain about the immune status of cific to a given pathogen as well as to the host the body. It is possible that the neural signa- response — that is, the nervous system may be tures encoded in these electrical signals are spe- able to discriminate not only the location of an 2132
n engl j med 371;22
nejm.org
november 27, 2014
The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on November 27, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
clinical implications of basic research
Figure 1 (facing page). Neuronal Sensing and Modulation of the Local Immune Environment. Subsets of sensory neurons can integrate information about the local infectious and inflammatory environment to modulate immune responses.2,3 Panel A is adapted from Chiu et al.2 Formylated peptides and α-hemolysin toxin from Staphylococcus aureus activate Nav1.8+ nociceptors through FPR1 and ADAM10, respectively. Neuronal activation leads to an axon–axon reflex (dashed black line) that results in signals propagating to nerve terminals and to the release of neuropeptides such as CGRP, galanin, and somatostatin. These mediators bind their receptors on infiltrating immune cells and modify the local inflammatory response. Panel B is adapted from Riol-Blanco et al.3 TRPV1+ Nav1.8+ nociceptors drive psoriasiform skin inflammation induced by topical imiquimod. These peripheral sensory nerves are in close proximity to interleukin-23–producing dermal dendritic cells. The interleukin-23 activates γδ T cells, which release interleukin-22 and interleukin-17; this culminates in skin inflammation and keratinocyte activation and proliferation. CNS denotes central nervous system.
infection but also the type of pathogen causing it. We hypothesize that capturing and decoding this information through nerve recordings will permit diagnosis and monitoring of the course of an infectious disease. Testing this hypothesis will require the expansion of domains in both medicine and engineering. Once available, a compendium of microbiologic electrical signatures might be extended to therapeutics, to provide personalized antibiotic, immune-modulating therapies or perhaps
even therapies delivered by replication of these signatures. As demonstrated by Chiu et al. and Riol-Blanco et al., the functional capacity of the sensory neurons themselves extends beyond simply reporting on environmental challenges and includes active immune-regulating effects. In principle, by combining the reading and writing of neural information, it may be possible to establish closed-loop systems that modulate inflammatory or immune responses to improve patient outcomes. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the Department of Anesthesia, University of Toronto (B.E.S.), and the Keenan Research Centre for Biomedical Science, St. Michael’s Hospital (A.S.S.) — both in Toronto; and the Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, NY (K.J.T.). 1. Kumar A, Roberts D, Wood KE, et al. Duration of hypoten-
sion before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006;34:1589-96. 2. Chiu IM, Heesters BA, Ghasemlou N, et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 2013;501:52-7. 3. Riol-Blanco L, Ordovas-Montanes J, Perro M, et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 2014;510:157-61. 4. Andersson U, Tracey KJ. Reflex principles of immunological homeostasis. Annu Rev Immunol 2012;30:313-35. 5. Watkins LR, Goehler LE, Relton JK, et al. Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication. Neurosci Lett 1995;183:27-31. DOI: 10.1056/NEJMcibr1412003 Copyright © 2014 Massachusetts Medical Society.
receive the journal’s table of contents each week by e-mail
To receive the table of contents of the Journal by e-mail every Wednesday evening, sign up at NEJM.org.
n engl j med 371;22 nejm.org november 27, 2014
2133
The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on November 27, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
