Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis
Sigma-1 receptor subdues systemic inflammation
Systemic inflammation can be lethal, as in the case of septic shock. Rosen et al. hypothesized that the endoplasmic reticulum, now understood to affect inflammation, could be an untapped therapeutic target. They found that mice lacking the endoplasmic reticulum sigma-1 receptor had exacerbated responses to LPS or fecal slurry. The antidepressant fluvoxamine can bind sigma-1 and acts as an agonist. Therapeutic treatment of mice in the two inflammatory models revealed that fluvoxamine lowered inflammatory cytokine production and improved survival. Their results suggest that repurposing fluvoxamine to enhance sigma-1 activity may be beneficial for treating sepsis.
Abstract
Sepsis is an often deadly complication of infection in which systemic inflammation damages the vasculature, leading to tissue hypoperfusion and multiple organ failure. Currently, the standard of care for sepsis is predominantly supportive, with few therapeutic options available. Because of increased sepsis incidence worldwide, there is an urgent need for discovery of novel therapeutic targets and development of new treatments. The recently discovered function of the endoplasmic reticulum (ER) in regulation of inflammation offers a potential avenue for sepsis control. Here, we identify the ER-resident protein sigma-1 receptor (S1R) as an essential inhibitor of cytokine production in a preclinical model of septic shock. Mice lacking S1R succumb quickly to hypercytokinemia induced by a sublethal challenge in two models of acute inflammation. Mechanistically, we find that S1R restricts the endonuclease activity of the ER stress sensor IRE1 and cytokine expression but does not inhibit the classical inflammatory signaling pathways. These findings could have substantial clinical implications, as we further find that fluvoxamine, an antidepressant therapeutic with high affinity for S1R, protects mice from lethal septic shock and dampens the inflammatory response in human blood leukocytes. Our data reveal the contribution of S1R to the restraint of the inflammatory response and place S1R as a possible therapeutic target to treat bacterial-derived inflammatory pathology.
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Supplementary Material
Summary
Fig. S1. S1R deletion influences a subset of LPS-induced processes without causing global perturbation.
Fig. S2. Canonical TLR4 signaling in macrophages is unperturbed by S1R deletion.
Fig. S3. Gating strategy and quantification of immunophenotyping on blood.
Fig. S4. Gating strategy and quantification of immunophenotyping on peritoneal contents.
Fig .S5. Gating strategy and quantification of immunophenotyping on spleen and lymph node.
Fig. S6. S1R controls inflammation in primary fibroblasts.
Fig. S7. STF affects cytokine production in vitro and in vivo.
Fig. S8. Anti-inflammatory effect of FLV does not globally suppress cytokine production from human blood.
Fig. S9. Proposed mechanism of action of S1R during LPS-mediated inflammatory response.
Data file S1. Primary data (Excel file).
Resources
REFERENCES AND NOTES
1
J. A. Cho, A. H. Lee, B. Platzer, B. C. S. Cross, B. M. Gardner, H. De Luca, P. Luong, H. P. Harding, L. H. Glimcher, P. Walter, E. Fiebiger, D. Ron, J. C. Kagan, W. I. Lencer, The unfolded protein response element IRE1α senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling. Cell Host Microbe 13, 558–569 (2013).
2
Q. Qiu, Z. Zheng, L. Chang, Y. S. Zhao, C. Tan, A. Dandekar, Z. Zhang, Z. Lin, M. Gui, X. Li, T. Zhang, Q. Kong, H. Li, S. Chen, A. Chen, R. J. Kaufman, W. L. Yang, H. K. Lin, D. Zhang, H. Perlman, E. Thorp, K. Zhang, D. Fang, Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis. EMBO J. 32, 2477–2490 (2013).
3
F. Martinon, X. Chen, A. H. Lee, L. H. Glimcher, TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat. Immunol. 11, 411–418 (2010).
4
J. R. Cubillos-Ruiz, P. C. Silberman, M. R. Rutkowski, S. Chopra, A. Perales-Puchalt, M. Song, S. Zhang, S. E. Bettigole, D. Gupta, K. Holcomb, L. H. Ellenson, T. Caputo, A. H. Lee, J. R. Conejo-Garcia, L. H. Glimcher, ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 161, 1527–1538 (2015).
5
F. Urano, X. Wang, A. Bertolotti, Y. Zhang, P. Chung, H. P. Harding, D. Ron, Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287, 664–666 (2000).
6
B. H. Abuaita, K. M. Burkholder, B. R. Boles, M. X. O’Riordan, The endoplasmic reticulum stress sensor inositol-requiring enzyme 1α augments bacterial killing through sustained oxidant production. MBio 6, e00705 (2015).
7
S. Fu, S. M. Watkins, G. S. Hotamisligil, The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab. 15, 623–634 (2012).
8
K. L. Lipson, S. G. Fonseca, S. Ishigaki, L. X. Nguyen, E. Foss, R. Bortell, A. A. Rossini, F. Urano, Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab. 4, 245–254 (2006).
9
T. Mori, T. Hayashi, E. Hayashi, T. P. Su, Sigma-1 receptor chaperone at the ER-mitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival. PLOS ONE 8, e76941 (2013).
10
B. Zhang, L. Wang, T. Chen, J. Hong, S. Sha, J. Wang, H. Xiao, L. Chen, Sigma-1 receptor deficiency reduces GABAergic inhibition in the basolateral amygdala leading to LTD impairment and depressive-like behaviors. Neuropharmacology 116, 387–398 (2017).
11
T. A. Mavlyutov, L. W. Guo, M. L. Epstein, A. E. Ruoho, Role of the Sigma-1 receptor in amyotrophic lateral sclerosis (ALS). J. Pharmacol. Sci. 127, 10–16 (2015).
12
T. Maurice, N. Goguadze, Sigma-1 (σ1) receptor in memory and neurodegenerative diseases. Handb. Exp. Pharmacol. 244, 81–108 (2017).
13
C. Moritz, F. Berardi, C. Abate, F. Peri, Live imaging reveals a new role for the sigma-1 (σ1) receptor in allowing microglia to leave brain injuries. Neurosci. Lett. 591, 13–18 (2015).
14
Y. Ha, A. K. Shanmugam, S. Markand, E. Zorrilla, V. Ganapathy, S. B. Smith, Sigma receptor 1 modulates ER stress and Bcl2 in murine retina. Cell Tissue Res. 356, 15–27 (2014).
15
A. Szabo, A. Kovacs, E. Frecska, E. Rajnavolgyi, Psychedelic N,N-Dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. PLOS ONE 9, e106533 (2014).
16
E. J. Cobos, J. M. Entrena, F. R. Nieto, C. M. Cendán, E. Del Pozo, Pharmacology and therapeutic potential of sigma(1) receptor ligands. Curr. Neuropharmacol. 6, 344–366 (2008).
17
T. Pozzobon, N. Facchinello, F. Bossi, N. Capitani, M. Benagiano, G. Di Benedetto, C. Zennaro, N. West, G. Codolo, M. Bernardini, C. T. Baldari, M. M. D'Elios, L. Pellegrini, F. Argenton, M. de Bernard, Treponema pallidum (syphilis) antigen TpF1 induces angiogenesis through the activation of the IL-8 pathway. Sci. Rep. 6, 18785 (2016).
18
K. J. Roux, D. I. Kim, M. Raida, B. Burke, A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells. J. Cell Biol. 196, 801–810 (2012).
19
B. C. Cross, P. J. Bond, P. G. Sadowski, B. K. Jha, J. Zak, J. M. Goodman, R. H. Silverman, T. A. Neubert, I. R. Baxendale, D. Ron, H. P. Harding, The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc. Natl. Acad. Sci. U.S.A. 109, E869–E878 (2012).
20
A. V. Korennykh, P. F. Egea, A. A. Korostelev, J. Finer-Moore, C. Zhang, K. M. Shokat, R. M. Stroud, P. Walter, The unfolded protein response signals through high-order assembly of Ire1. Nature 457, 687–693 (2009).
21
S. Copeland, H. S. Warren, S. F. Lowry, S. E. Calvano, D. Remick, Acute inflammatory response to endotoxin in mice and humans. Clin. Diagn. Lab. Immunol. 12, 60–67 (2005).
22
S. Oda, H. Hirasawa, H. Shiga, K. Nakanishi, K. Matsuda, M. Nakamua, Sequential measurement of IL-6 blood levels in patients with systemic inflammatory response syndrome (SIRS)/sepsis. Cytokine 29, 169–175 (2005).
23
C. M. Oslowski, F. Urano, Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Methods Enzymol. 490, 71–92 (2011).
24
A. J. Lewis, C. W. Seymour, M. R. Rosengart, Current murine models of sepsis. Surg. Infect. 17, 385–393 (2016).
25
D. G. Remick, G. R. Bolgos, J. Siddiqui, J. Shin, J. A. Nemzek, Six at six: Interleukin-6 measured 6 h after the initiation of sepsis predicts mortality over 3 days. Shock 17, 463–467 (2002).
26
B. Shrum, R. V. Anantha, S. X. Xu, M. Donnelly, S. M. M. Haeryfar, J. K. McCormick, T. Mele, A robust scoring system to evaluate sepsis severity in an animal model. BMC. Res. Notes 7, 233 (2014).
27
I. Papandreou, N. C. Denko, M. Olson, H. Van Melckebeke, S. Lust, A. Tam, D. E. Solow-Cordero, D. M. Bouley, F. Offner, M. Niwa, A. C. Koong, Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood 117, 1311–1314 (2011).
28
M. Ghareghani, K. Zibara, H. Sadeghi, S. Dokoohaki, H. Sadeghi, R. Aryanpour, A. Ghanbari, Fluvoxamine stimulates oligodendrogenesis of cultured neural stem cells and attenuates inflammation and demyelination in an animal model of multiple sclerosis. Sci. Rep. 7, 4923 (2017).
29
M. T. Foster Jr., Ceftriaxone in treatment of serious infections. Septicemia. Hosp. Pract. 26 (suppl. 5), 43–47 (1991).
30
S. Janssens, B. Pulendran, B. N. Lambrecht, Emerging functions of the unfolded protein response in immunity. Nat. Immunol. 15, 910–919 (2014).
31
M. M. Levy, M. P. Fink, J. C. Marshall, E. Abraham, D. Angus, D. Cook, J. Cohen, S. M. Opal, J.-L. Vincent, G. Ramsay, 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit. Care Med. 31, 1250–1256 (2003).
32
E. E. Davenport, K. L. Burnham, J. Radhakrishnan, P. Humburg, P. Hutton, T. C. Mills, A. Rautanen, A. C. Gordon, C. Garrard, A. V. S. Hill, C. J. Hinds, J. C. Knight, Genomic landscape of the individual host response and outcomes in sepsis: A prospective cohort study. Lancet Respir. Med. 4, 259–271 (2016).
33
S. B. Hu, A. Zider, J. C. Deng, When host defense goes awry: Modeling sepsis-induced immunosuppression. Drug Discov. Today Dis. Models 9, e33–e38 (2012).
34
A. Salminen, A. Kauppinen, T. Suuronen, K. Kaarniranta, J. Ojala, ER stress in Alzheimer's disease: A novel neuronal trigger for inflammation and Alzheimer's pathology. J. Neuroinflammation 6, 41 (2009).
35
A. Marrazzo, F. Caraci, E. T. Salinaro, T.-P. Su, A. Copani, G. Ronsisvalle, Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity. Neuroreport 16, 1223–1226 (2005).
36
H. Kikuchi, G. Almer, S. Yamashita, C. Guégan, M. Nagai, Z. Xu, A. A. Sosunov, G. M. McKhann II, S. Przedborski, Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. Proc. Natl. Acad. Sci. U.S.A. 103, 6025–6030 (2006).
37
T. Hayashi, T.-P. Su, Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell 131, 596–610 (2007).
38
D. Fontanilla, M. Johannessen, A. R. Hajipour, N. V. Cozzi, M. B. Jackson, A. E. Ruoho, The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator. Science 323, 934–937 (2009).
39
M. S. Shajib, W. I. Khan, The role of serotonin and its receptors in activation of immune responses and inflammation. Acta Physiol. 213, 561–574 (2015).
40
Y. Ha, A. Saul, A. Tawfik, C. Williams, K. Bollinger, R. Smith, M. Tachikawa, E. Zorrilla, V. Ganapathy, S. B. Smith, Late-onset inner retinal dysfunction in mice lacking sigma receptor 1 (σR1). Invest. Ophthalmol. Vis. Sci. 52, 7749–7760 (2011).
41
V. Sabino, P. Cottone, S. L. Parylak, L. Steardo, E. P. Zorrilla, Sigma-1 receptor knockout mice display a depressive-like phenotype. Behav. Brain Res. 198, 472–476 (2009).
42
A. Seluanov, A. Vaidya, V. Gorbunova, Establishing primary adult fibroblast cultures from rodents. J. Vis. Exp. 44, 2033 (2010).
43
X. Zhang, R. Goncalves, D. M. Mosser, The isolation and characterization of murine macrophages. Curr. Protoc. Immunol. 83, 14.1.1–14.1.14 (2008).
44
A. Gaultier, S. Arandjelovic, S. Niessen, C. D. Overton, M. F. Linton, S. Fazio, W. M. Campana, B. F. Cravatt III, S. L. Gonias, Regulation of tumor necrosis factor receptor-1 and the IKK-NF-κB pathway by LDL receptor–related protein explains the antiinflammatory activity of this receptor. Blood 111, 5316–5325 (2008).
45
C. A. Girard, F. T. Wunderlich, K. Shimomura, S. Collins, S. Kaizik, P. Proks, F. Abdulkader, A. Clark, V. Ball, L. Zubcevic, L. Bentley, R. Clark, C. Church, A. Hugill, J. Galvanovskis, R. Cox, P. Rorsman, J. C. Brüning, F. M. Ashcroft, Expression of an activating mutation in the gene encoding the KATP channel subunit Kir6.2 in mouse pancreatic beta cells recapitulates neonatal diabetes. J. Clin. Invest. 119, 80–90 (2009).
46
Y. Kumar, R. H. Valdivia, Actin and intermediate filaments stabilize the Chlamydia trachomatis vacuole by forming dynamic structural scaffolds. Cell Host Microbe 4, 159–169 (2008).
47
J. Vandesompele, K. De Preter, F. Pattyn, B. Poppe, N. Van Roy, A. De Paepe, F. Speleman, Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 3, RESEARCH0034 (2002).
48
S. M. Seki, M. Stevenson, A. M. Rosen, S. Arandjelovic, L. Gemta, T. N. J. Bullock, A. Gaultier, Lineage-specific metabolic properties and vulnerabilities of T cells in the demyelinating central nervous system. J. Immunol. 198, 4607–4617 (2017).
49
C. W. Thurm, J. F. Halsey, Measurement of cytokine production using whole blood. Curr. Protoc. Immunol. 66, 7.18B.1–7.18B.12 (2005).
Information & Authors
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Published In
Science Translational Medicine
Volume 11 | Issue 478
February 2019
February 2019
Copyright
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
This is an article distributed under the terms of the Science Journals Default License.
Submission history
Received: 19 June 2018
Accepted: 15 January 2019
Acknowledgments
We thank S. Arandjelovic and the BIG center (University of Virginia) for critical reading of the manuscript. Funding: The authors are supported by NIH grants R01 NS083542 and R21 NS101281 (to A.G.), the Owens Family Foundation (to A.G.), and T32 GM007055 (to D.A.R.). Author contributions: D.A.R. designed, performed, and analyzed the research and wrote the paper. S.M.S., A.F.-C., J.D.E., R.M.B., and J.A.W. performed the research. A.G. designed and analyzed the research and wrote the paper. Competing interests: D.A.R. and A.G. are inventors on U.S. Provisional patent application no. 62/618,741 submitted by the University of Virginia entitled “Compositions and Methods for Regulating Inflammation.” The authors declare that they have no other competing interests. Data and materials availability: All data related to this study can be found in the paper and the Supplementary Materials.
Authors
Funding Information
National Institute of General Medical Sciences: T32 GM007055
National Institute of Neurological Disorders and Stroke: R01 NS083542
National Institute of Neurological Disorders and Stroke: R21 NS101281
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