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The greater inflammatory pathway—high clinical potential by innovative predictive, preventive, and personalized medical approach

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Abstract

Background and limitations

Impaired wound healing (WH) and chronic inflammation are hallmarks of non-communicable diseases (NCDs). However, despite WH being a recognized player in NCDs, mainstream therapies focus on (un)targeted damping of the inflammatory response, leaving WH largely unaddressed, owing to three main factors. The first is the complexity of the pathway that links inflammation and wound healing; the second is the dual nature, local and systemic, of WH; and the third is the limited acknowledgement of genetic and contingent causes that disrupt physiologic progression of WH.

Proposed approach

Here, in the frame of Predictive, Preventive, and Personalized Medicine (PPPM), we integrate and revisit current literature to offer a novel systemic view on the cues that can impact on the fate (acute or chronic inflammation) of WH, beyond the compartmentalization of medical disciplines and with the support of advanced computational biology.

Conclusions

This shall open to a broader understanding of the causes for WH going awry, offering new operational criteria for patients’ stratification (prediction and personalization). While this may also offer improved options for targeted prevention, we will envisage new therapeutic strategies to reboot and/or boost WH, to enable its progression across its physiological phases, the first of which is a transient acute inflammatory response versus the chronic low-grade inflammation characteristic of NCDs.

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Abbreviations

ANS:

Autonomic nervous system

AR:

Adrenoceptor

BMI:

Body mass index

CNS:

Central nervous system

CRP:

C-reactive protein

DVC:

Dorsal vagal complex

ECM:

Extracellular matrix

EMT:

Epithelial-mesenchymal transition

ENS:

Enteric nervous system

ESWT:

Extracorporeal shock wave therapy

FMT:

Fecal microbiota transplantation

GBA:

Gut-brain axis

GI:

Gut-intestinal

GWAS:

Genome-wide association studies

HPA:

Hypothalamus-pituitary-adrenal

LC:

Locus coeruleus

NCD:

Non-communicable disease

NTS:

Nucleus tractus solitarii

PPPM:

Predictive, preventive, and personalized medicine

PRS:

Polygenic Risk Scores

PVN:

Paraventricular nuclei

RA:

Rheumatoid arthritis

RVLM:

Rostroventrolateral medulla

SBML:

Systems Biology Markup Language

SNS:

Sympathetic nervous system

TNF:

Tumor necrosis factor

WH:

Wound healing

WHO:

World Health Organization

References

  1. Latifi R, editor. The modern hospital: patients centered, disease based, research oriented, technology driven. Cham: Springer International Publishing; 2019. ISBN 978-3-030-01393-6

    Google Scholar 

  2. Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK, et al. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen Off Publ Wound Heal Soc Eur Tissue Repair Soc. 2009;17:763–71.

    Google Scholar 

  3. GBD 2015. Risk Factors Collaborators Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Lond Engl. 2016;388:1659–724.

    Article  Google Scholar 

  4. Avishai E, Yeghiazaryan K, Golubnitschaja O. Impaired wound healing: facts and hypotheses for multi-professional considerations in predictive, preventive and personalised medicine. EPMA J. 2017;8:23–33.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Stolzenburg-Veeser L, Golubnitschaja O. Mini-encyclopaedia of the wound healing - opportunities for integrating multi-omic approaches into medical practice. J Proteome. 2018;188:71–84.

    Article  CAS  Google Scholar 

  6. Boniakowski AE, Kimball AS, Jacobs BN, Kunkel SL, Gallagher KA. Macrophage-mediated inflammation in normal and diabetic wound healing. J Immunol Baltim Md 1950. 2017;199:17–24.

    CAS  Google Scholar 

  7. Landén NX, Li D, Ståhle M. Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci CMLS. 2016;73:3861–85.

    Article  PubMed  CAS  Google Scholar 

  8. Tracey KJ. The inflammatory reflex. Nature. 2002;420:853–9.

    Article  CAS  PubMed  Google Scholar 

  9. Pongratz G, Straub RH. The sympathetic nervous response in inflammation. Arthritis Res Ther. 2014;16:504.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Valero C, Javierre E, García-Aznar JM, Gómez-Benito MJ. A cell-regulatory mechanism involving feedback between contraction and tissue formation guides wound healing progression. PLoS One. 2014;9:e92774.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Kenny FN, Connelly JT. Integrin-mediated adhesion and mechano-sensing in cutaneous wound healing. Cell Tissue Res. 2015;360:571–82.

    Article  CAS  PubMed  Google Scholar 

  12. Szczęsny G. Fracture Healing and its disturbances. A literature review. Ortop Traumatol Rehabil. 2015;17:437–54.

    Article  PubMed  Google Scholar 

  13. Cho YS, Joo SY, Cui H, Cho S-R, Yim H, Seo CH. Effect of extracorporeal shock wave therapy on scar pain in burn patients: a prospective, randomized, single-blind, placebo-controlled study. Medicine (Baltimore). 2016;95:e4575.

    Article  Google Scholar 

  14. Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2016;113:8284–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fernandez-Sanchez ME, Barbier S, Whitehead J, Bealle G, Michel A, Latorre-Ossa H, et al. Mechanical induction of the tumorigenic beta-catenin pathway by tumour growth pressure. Nature. 2015;523:92–5.

    Article  CAS  PubMed  Google Scholar 

  16. Serra MB, Barroso WA, da Silva NN, Silva S d N, Borges ACR, Abreu IC, et al. From inflammation to current and alternative therapies involved in wound healing. Int J Inflamm. 2017;2017:1–17.

    Article  CAS  Google Scholar 

  17. Ligthart S, Vaez A, Võsa U, Stathopoulou MG, de Vries PS, Prins BP, et al. Genome analyses of >200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders. Am J Hum Genet. 2018;103:691–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cheng L, Zhuang H, Yang S, Jiang H, Wang S, Zhang J. Exposing the causal effect of C-reactive protein on the risk of type 2 diabetes mellitus: a Mendelian randomization study. Front Genet. 2018;9:657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119:1420–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014;7:re8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Cordeiro JV, Jacinto A. The role of transcription-independent damage signals in the initiation of epithelial wound healing. Nat Rev Mol Cell Biol; England. 2013;14:249–62 ISBN 1471-0080 (Electronic) 1471-0072 (Linking).

    Article  CAS  Google Scholar 

  23. Silver FH, Silver LL. Gravity, mechanotransduction and healing: how mechanical forces promote tissue repair. SM J Biomed Eng. 2017; 3(4):1023.

  24. Na S, Collin O, Chowdhury F, Tay B, Ouyang M, Wang Y, et al. Rapid signal transduction in living cells is a unique feature of mechanotransduction. Proc Natl Acad Sci U S A. 2008;105:6626–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Meyer M, McGrouther DA. A study relating wound tension to scar morphology in the pre-sternal scar using Langers technique. Br J Plast Surg. 1991;44:291–4.

    Article  CAS  PubMed  Google Scholar 

  26. Gurtner GC, Dauskardt RH, Wong VW, Bhatt KA, Wu K, Vial IN, et al. Improving cutaneous scar formation by controlling the mechanical environment: large animal and phase I studies. Ann Surg. 2011;254:217–25.

    Article  PubMed  Google Scholar 

  27. Ng JL, Kersh ME, Kilbreath S, Knothe Tate M. Establishing the basis for mechanobiology-based physical therapy protocols to potentiate cellular healing and tissue regeneration. Front Physiol. 2017;8:303.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Barnes LA, Marshall CD, Leavitt T, Hu MS, Moore AL, Gonzalez JG, et al. Mechanical forces in cutaneous wound healing: emerging therapies to minimize scar formation. Adv Wound Care. 2018;7:47–56.

    Article  Google Scholar 

  29. Hausner T, Nógrádi A. The use of shock waves in peripheral nerve regeneration: new perspectives? Int Rev Neurobiol. 2013;109:85–98.

    Article  PubMed  Google Scholar 

  30. Davis TA, Stojadinovic A, Anam K, Amare M, Naik S, Peoples GE, et al. Extracorporeal shock wave therapy suppresses the early proinflammatory immune response to a severe cutaneous burn injury. Int Wound J. 2009;6:11–21.

    Article  PubMed  Google Scholar 

  31. Kuo Y-R, Wang C-T, Wang F-S, Chiang Y-C, Wang C-J. Extracorporeal shock-wave therapy enhanced wound healing via increasing topical blood perfusion and tissue regeneration in a rat model of STZ-induced diabetes. Wound Repair Regen. 2009;17:522–30.

    Article  PubMed  Google Scholar 

  32. Sukubo NG, Tibalt E, Respizzi S, Locati M, d’Agostino MC. Effect of shock waves on macrophages: a possible role in tissue regeneration and remodeling. Int J Surg. 2015;24:124–30.

    Article  PubMed  Google Scholar 

  33. Viganò M, Sansone V, d’Agostino MC, Romeo P, Perucca Orfei C, de Girolamo L. Mesenchymal stem cells as therapeutic target of biophysical stimulation for the treatment of musculoskeletal disorders. J Orthop Surg. 2016;11:163.

    Article  Google Scholar 

  34. Waters-Banker C, Dupont-Versteegden EE, Kitzman PH, Butterfield TA. Investigating the mechanisms of massage efficacy: the role of mechanical immunomodulation. J Athl Train. 2014;49:266–73.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Rosińczuk J, Taradaj J, Dymarek R, Sopel M. Mechanoregulation of wound healing and skin homeostasis. Biomed Res Int. 2016;2016:1–13.

    Article  CAS  Google Scholar 

  36. Besedovsky H, del Rey A, Sorkin E, Dinarello CA. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science. 1986;233:652–4.

    Article  CAS  PubMed  Google Scholar 

  37. Zielinski MR, Dunbrasky DL, Taishi P, Souza G, Krueger JM. Vagotomy attenuates brain cytokines and sleep induced by peripherally administered tumor necrosis factor-α and lipopolysaccharide in mice. Sleep. 2013;36:1227–38.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Edoff K, Jerregard H. Effects of IL-1beta, IL-6 or LIF on rat sensory neurons co-cultured with fibroblast-like cells. J Neurosci Res. 2002;67:255–63.

    Article  CAS  PubMed  Google Scholar 

  39. Hosoi T, Okuma Y, Matsuda T, Nomura Y. Novel pathway for LPS-induced afferent vagus nerve activation: possible role of nodose ganglion. Auton Neurosci. 2005;120:104–7.

    Article  CAS  PubMed  Google Scholar 

  40. Nicol GD, Lopshire JC, Pafford CM. Tumor necrosis factor enhances the capsaicin sensitivity of rat sensory neurons. J Neurosci. 1997;17(17):975–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Safieh-Garabedian B, Poole S, Allchorne A, Winter J, Woolf CJ. Contribution of interleukin-1 beta to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia. Br J Pharmacol. 1995;115(115):1265–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Donnerer J, Amann R, Lembeck F. Neurogenic and non-neurogenic inflammation in the rat paw following chemical sympathectomy. Neuroscience. 1991;45(45):761-5-761–5.

    Google Scholar 

  43. Pinter E, Szolcsanyi J. Systemic anti-inflammatory effect induced by antidromic stimulation of the dorsal roots in the rat. Neurosci Lett. 1996;212(212):33–6.

    Article  CAS  PubMed  Google Scholar 

  44. Sann H, Pierau FK. Efferent functions of C-fiber nociceptors. Z Rheumatol. 1998;57 Suppl 2(57 Suppl 2):8–13 8–13.

    Article  CAS  PubMed  Google Scholar 

  45. Sato A, Sato Y, Shimura M, Uchida S. Calcitonin gene-related peptide produces skeletal muscle vasodilation following antidromic stimulation of unmyelinated afferents in the dorsal root in rats. Neurosci Lett. 2000;283:137–40.

    Article  CAS  PubMed  Google Scholar 

  46. Nance DM, Sanders VM. Autonomic innervation and regulation of the immune system (1987-2007). Brain Behav Immun. 2007;21:736–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Scheiermann C, Kunisaki Y, Lucas D, Chow A, Jang J-E, Zhang D, et al. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity. 2012;37:290–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Powell ND, Sloan EK, Bailey MT, Arevalo JMG, Miller GE, Chen E, et al. Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via -adrenergic induction of myelopoiesis. Proc Natl Acad Sci. 2013;110:16574–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Merhi M, Helme RD, Khalil Z. Age-related changes in sympathetic modulation of sensory nerve activity in rat skin. Inflamm Res. 1998;47:239–44.

    Article  CAS  PubMed  Google Scholar 

  50. Dawson LF, Phillips JK, Finch PM, Inglis JJ, Drummond PD. Expression of α1-adrenoceptors on peripheral nociceptive neurons. Neuroscience. 2011;175:300–14.

    Article  CAS  PubMed  Google Scholar 

  51. Andersson U, Tracey KJ. Reflex principles of immunological homeostasis. Annu Rev Immunol. 2012;30:313–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Martelli D, Yao ST, McKinley MJ, McAllen RM. Reflex control of inflammation by sympathetic nerves, not the vagus. J Physiol. 2014;592:1677–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Martelli D, Farmer DG, Yao ST. The splanchnic anti-inflammatory pathway: could it be the efferent arm of the inflammatory reflex? Exp Physiol. 2016;101:1245–52.

    Article  CAS  PubMed  Google Scholar 

  54. Borovikova LV, Ivanova S, Nardi D, Zhang M, Yang H, Ombrellino M, et al. Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation. Auton Neurosci. 2000;85:141–7.

    Article  CAS  PubMed  Google Scholar 

  55. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–62.

    Article  CAS  PubMed  Google Scholar 

  56. Vida G, Pena G, Deitch EA, Ulloa L. alpha7-Cholinergic receptor mediates vagal induction of splenic norepinephrine. J Immunol. 2011;186:4340–6.

    Article  CAS  PubMed  Google Scholar 

  57. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421:384–8.

    Article  CAS  PubMed  Google Scholar 

  58. Rosas-Ballina M, Olofsson PS, Ochani M, Valdes-Ferrer SI, Levine YA, Reardon C, et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011;334:98–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Martelli D, McKinley MJ, McAllen RM. The cholinergic anti-inflammatory pathway: a critical review. Auton Neurosci. 2014;182:65–9.

    Article  CAS  PubMed  Google Scholar 

  60. Rosas-Ballina M, Ochani M, Parrish WR, Ochani K, Harris YT, Huston JM, et al. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc Natl Acad Sci U S A. 2008;105:11008–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Murray K, Reardon C. The cholinergic anti-inflammatory pathway revisited. Neurogastroenterol Motil. 2018;30:e13288.

    Article  CAS  Google Scholar 

  62. McAllen RM, Cook AD, Khiew HW, Martelli D, Hamilton JA. The interface between cholinergic pathways and the immune system and its relevance to arthritis. Arthritis Res Ther. 2015;17:87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Pereira MR, Leite PE. The involvement of parasympathetic and sympathetic nerve in the inflammatory reflex. J Cell Physiol. 2016;231:1862–9.

    Article  CAS  PubMed  Google Scholar 

  64. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature; 2000;405:458-62

    Article  CAS  PubMed  Google Scholar 

  65. Bernik TR, Friedman SG, Ochani M, DiRaimo R, Ulloa L, Yang H, et al. Pharmacological stimulation of the cholinergic antiinflammatory pathway. J Exp Med. 2002;195:781–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28:203–9.

    PubMed  PubMed Central  Google Scholar 

  67. Fung TC, Olson CA, Hsiao EY. Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci. 2017;20:145–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Montiel-Castro AJ, Gonzalez-Cervantes RM, Bravo-Ruiseco G, Pacheco-Lopez G. The microbiota-gut-brain axis: neurobehavioral correlates, health and sociality. Front Integr Neurosci. 2013;7:70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Choi HH, Cho Y-S. Fecal microbiota transplantation: current applications, effectiveness, and future perspectives. Clin Endosc. 2016;49:257–65.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Tremlett H, Bauer KC, Appel-Cresswell S, Finlay BB, Waubant E. The gut microbiome in human neurological disease: a review. Ann Neurol. 2017;81:369–82.

    Article  PubMed  Google Scholar 

  71. Clemente JC, Manasson J, Scher JU. The role of the gut microbiome in systemic inflammatory disease. BMJ. 2018;360:j5145.

    Article  PubMed  PubMed Central  Google Scholar 

  72. de Oliveira GLV, Leite AZ, Higuchi BS, Gonzaga MI, Mariano VS. Intestinal dysbiosis and probiotic applications in autoimmune diseases. Immunology. 2017;152:1–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Chen B, Sun L, Zhang X. Integration of microbiome and epigenome to decipher the pathogenesis of autoimmune diseases. J Autoimmun. 2017;83:31–42.

    Article  CAS  PubMed  Google Scholar 

  74. Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E. Dysbiosis and the immune system. Nat Rev Immunol. 2017;17:219–32.

    Article  CAS  PubMed  Google Scholar 

  75. Bornigen D, Morgan XC, Franzosa EA, Ren B, Xavier RJ, Garrett WS, et al. Functional profiling of the gut microbiome in disease-associated inflammation. Genome Med. 2013;5:65.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A, Wargo JA. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell. 2018;33:570–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Honda K, Littman DR. The microbiome in infectious disease and inflammation. Annu Rev Immunol. 2012;30:759–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Scher JU, Abramson SB. The microbiome and rheumatoid arthritis. Nat Rev Rheumatol; United States. 2011;7:569–78 ISBN 1759-4804 (Electronic) 1759-4790 (Linking).

    Article  CAS  Google Scholar 

  79. Li J, Chen J, Kirsner R. Pathophysiology of acute wound healing. Clin Dermatol. 2007;25:9–18.

    Article  CAS  PubMed  Google Scholar 

  80. Karin M, Clevers H. Reparative inflammation takes charge of tissue regeneration. Nature. 2016;529:307–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chavan SS, Tracey KJ. Essential neuroscience in immunology. J Immunol. 2017;198:3389–97.

    Article  CAS  PubMed  Google Scholar 

  82. Pavlov VA, Chavan SS, Tracey KJ. Molecular and functional neuroscience in immunity. Annu Rev Immunol. 2018;36:783–812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhao R, Liang H, Clarke E, Jackson C, Xue M. Inflammation in chronic wounds. Int J Mol Sci. 2016;17(12). https://doi.org/10.3390/ijms17122085.

    Article  PubMed Central  CAS  Google Scholar 

  84. Goldstein DS, Kopin IJ. Homeostatic systems, biocybernetics, and autonomic neuroscience. Auton Neurosci. 2017;208:15–28.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Reardon C. Neuro-immune interactions in the cholinergic anti-inflammatory reflex. Immunol Lett. 2016;178:92–6.

    Article  CAS  PubMed  Google Scholar 

  86. Chavan SS, Pavlov VA, Tracey KJ. Mechanisms and therapeutic relevance of neuro-immune communication. Immunity. 2017;46:927–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hoover DB. Cholinergic modulation of the immune system presents new approaches for treating inflammation. Pharmacol Ther. 2017;179:1–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zila I, Mokra D, Kopincova J, Kolomaznik M, Javorka M, Calkovska A. Vagal-immune interactions involved in cholinergic anti-inflammatory pathway. Physiol Res. 2017;66:S139–45.

    Article  CAS  PubMed  Google Scholar 

  89. Ulloa L, Quiroz-Gonzalez S, Torres-Rosas R. Nerve stimulation: immunomodulation and control of inflammation. Trends Mol Med. 2017;23:1103–20.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin Invest. 2010;120:3779–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Berthoud HR, Neuhuber WL. Functional and chemical anatomy of the afferent vagal system. Auton Neurosci. 2000;85:1–17.

    Article  CAS  PubMed  Google Scholar 

  92. Goehler LE, Gaykema RP, Opitz N, Reddaway R, Badr N, Lyte M. Activation in vagal afferents and central autonomic pathways: early responses to intestinal infection with Campylobacter jejuni. Brain Behav Immun. 2005;19:334–44.

    Article  PubMed  Google Scholar 

  93. Kanashiro A, Shimizu Bassi G, de Queiroz Cunha F, Ulloa L. From neuroimunomodulation to bioelectronic treatment of rheumatoid arthritis. Bioelectron Med Lond. 2018;1:151–65.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Bassi GS, Dias DPM, Franchin M, Talbot J, Reis DG, Menezes GB, et al. Modulation of experimental arthritis by vagal sensory and central brain stimulation. Brain Behav Immun. 2017;64:330–43.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Lehner KR, Silverman HA, Addorisio ME, Roy A, Al-Onaizi MA, Levine Y, et al. Forebrain cholinergic signaling regulates innate immune responses and inflammation. Front Immunol. 2019;10:585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Abe C, Inoue T, Inglis MA, Viar KE, Huang L, Ye H, et al. C1 neurons mediate a stress-induced anti-inflammatory reflex in mice. Nat Neurosci. 2017;20:700–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ben-Shaanan TL, Azulay-Debby H, Dubovik T, Starosvetsky E, Korin B, Schiller M, et al. Activation of the reward system boosts innate and adaptive immunity. Nat Med. 2016;22:940–4.

    Article  CAS  PubMed  Google Scholar 

  98. Zhao Y, Forst CV, Sayegh CE, Wang I-M, Yang X, Zhang B. Molecular and genetic inflammation networks in major human diseases. Mol BioSyst. 2016;12:2318–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Somineni HK, Venkateswaran S, Kilaru V, Marigorta UM, Mo A, Okou DT, et al. Blood-derived DNA methylation signatures of Crohn’s disease and severity of intestinal inflammation. Gastroenterology. 2019;156:2254–2265.e3.

    Article  CAS  PubMed  Google Scholar 

  100. Ligthart S, Marzi C, Aslibekyan S, Mendelson MM, Conneely KN, Tanaka T, et al. DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. Genome Biol. 2016;17:255.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Wahl S, Drong A, Lehne B, Loh M, Scott WR, Kunze S, et al. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature. 2017;541:81–6.

    Article  CAS  PubMed  Google Scholar 

  102. Chen L, Ge B, Casale FP, Vasquez L, Kwan T, Garrido-Martín D, et al. Genetic drivers of epigenetic and transcriptional variation in human immune cells. Cell. 2016;167:1398–1414.e24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ventham NT, Kennedy NA, Adams AT, Kalla R, Heath S, O’Leary KR, et al. Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease. Nat Commun. 2016;7:13507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Castiglione F, Pappalardo F, Bianca C, Russo G, Motta S. Modeling biology spanning different scales: an open challenge. Biomed Res Int. 2014;2014:902545.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Ahn AC, Tewari M, Poon CS, Phillips RS. The limits of reductionism in medicine: could systems biology offer an alternative? PLoS Med; United States. 2006;3:e208 ISBN 1549-1676 (Electronic) 1549-1277 (Linking).

    Article  Google Scholar 

  106. Kitano H. Systems biology: a brief overview. Science; United States. 2002;295:1662–4 ISBN 1095-9203 (Electronic) 0036-8075 (Linking).

    CAS  Google Scholar 

  107. Golubnitschaja O, Baban B, Boniolo G, Wang W, Bubnov R, Kapalla M, et al. Medicine in the early twenty-first century: paradigm and anticipation - EPMA position paper 2016. EPMA J. 2016;7:23.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Erola P, Bonnet E, Michoel T. Learning differential module networks across multiple experimental conditions. Methods Mol Biol Clifton NJ. 1883;2019:303–21.

    Google Scholar 

  109. Segal E, Shapira M, Regev A, Pe’er D, Botstein D, Koller D, et al. Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data. Nat Genet; United States. 2003;34:166–76 ISBN 1061-4036 (Print) 1061-4036 (Linking).

    Article  CAS  Google Scholar 

  110. Zarayeneh N, Ko E, Oh JH, Suh S, Liu C, Gao J, et al. Integration of multi-omics data for integrative gene regulatory network inference. Int J Data Min Bioinforma. 2017;18:223–39.

    Article  Google Scholar 

  111. Sun YV, Hu Y-J. Integrative analysis of multi-omics data for discovery and functional studies of complex human diseases. Adv Genet. 2016;93:147–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Chaouiya C. Petri net modelling of biological networks. Brief Bioinform. 2007;8:210–9.

    Article  CAS  PubMed  Google Scholar 

  113. Irurzun-Arana I, Pastor JM, Trocóniz IF, Gómez-Mantilla JD. Advanced Boolean modeling of biological networks applied to systems pharmacology. Bioinforma Oxf Engl. 2017;33:1040–8.

    CAS  Google Scholar 

  114. Xing L, Guo M, Liu X, Wang C, Wang L, Zhang Y. An improved Bayesian network method for reconstructing gene regulatory network based on candidate auto selection. BMC Genomics. 2017;18:844.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Castiglione F, Tieri P, Palma A, Jarrah AS. Statistical ensemble of gene regulatory networks of macrophage differentiation. BMC Bioinformatics. 2016;17:506.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Dent JE, Nardini C. From desk to bed: computational simulations provide indication for rheumatoid arthritis clinical trials. BMC Syst Biol. 2013;7:10 ISBN 1752-0509 (Electronic) 1752-0509 (Linking).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Coker EA, Mitsopoulos C, Workman P, Al-Lazikani B. SiGNet: a signaling network data simulator to enable signaling network inference. PLoS One. 2017;12:e0177701.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Rubinstein A, Bracha N, Rudner L, Zucker N, Sloin HE, Chor B. BioNSi: a discrete biological network simulator tool. J Proteome Res. 2016;15:2871–80.

    Article  CAS  PubMed  Google Scholar 

  119. Marini S, Trifoglio E, Barbarini N, Sambo F, Di Camillo B, Malovini A, et al. A dynamic Bayesian network model for long-term simulation of clinical complications in type 1 diabetes. J Biomed Inform. 2015;57:369–76.

    Article  PubMed  Google Scholar 

  120. Beckett SJ. Improved community detection in weighted bipartite networks. R Soc Open Sci. 2016;3:140536.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Sung J, Kim S, Cabatbat JJT, Jang S, Jin YS, Jung GY, et al. Global metabolic interaction network of the human gut microbiota for context-specific community-scale analysis. Nat Commun. 2017;8:15393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Xie J-R, Zhang P, Zhang H-F, Wang B-H. Completeness of community structure in networks. Sci Rep. 2017;7:5269.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Lai D, Nardini C, Lu H. Partitioning networks into communities by message passing. Phys Rev E Stat Nonlinear Soft Matter Phys. 2011;83:016115.

    Article  CAS  Google Scholar 

  124. Boudin F. A comparison of centrality measures for graph-based keyphrase extraction. In-ternational Joint Conference on Natural Language Processing (IJCNLP), Oct 2013, Nagoya, Japan. pp. 834–8. hal-00850187.

  125. Assenov Y, Ramirez F, Schelhorn SE, Lengauer T, Albrecht M. Computing topological parameters of biological networks. Bioinformatics. 2008;24:282–4.

    Article  CAS  PubMed  Google Scholar 

  126. Kivimäki I, Lebichot B, Saramäki J, Saerens M. Two betweenness centrality measures based on Randomized Shortest Paths. Sci Rep. 2016;6:19668.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Hucka M, Finney A, Bornstein BJ, Keating SM, Shapiro BE, Matthews J, et al. Evolving a lingua franca and associated software infrastructure for computational systems biology: the Systems Biology Markup Language (SBML) project. Syst Biol Stevenage. 2004;1:41–53.

    Article  CAS  PubMed  Google Scholar 

  128. Dent JE, Devescovi V, Li H, Di Lena P, Lu Y, Liu Y, et al. Mechanotransduction map: simulation model, molecular pathway, gene set. Bioinformatics. 2015;31(7):1053–9.

    Article  PubMed  CAS  Google Scholar 

  129. Adra S, Sun T, MacNeil S, Holcombe M, Smallwood R. Development of a three dimensional multiscale computational model of the human epidermis. PLoS One. 2010;5:e8511.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Sun T, Adra S, Smallwood R, Holcombe M, MacNeil S. Exploring hypotheses of the actions of TGF-β1 in epidermal wound healing using a 3D computational multiscale model of the human epidermis. PLoS One. 2009;4:e8515.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Greenblum S, Turnbaugh PJ, Borenstein E. Metagenomic systems biology of the human gut microbiome reveals topological shifts associated with obesity and inflammatory bowel disease. Proc Natl Acad Sci U S A. 2012;109:594–9.

    Article  CAS  PubMed  Google Scholar 

  132. Tieri P, Zhou X, Zhu L, Nardini C. Multi-omic landscape of rheumatoid arthritis: re-evaluation of drug adverse effects. Front Cell Dev Biol. 2014;2:59.

  133. Bergthaler A, Menche J. The immune system as a social network. Nat Immunol. 2017;18:481–2.

    Article  CAS  PubMed  Google Scholar 

  134. Ghiassian SD, Menche J, Chasman DI, Giulianini F, Wang R, Ricchiuto P, et al. Endophenotype network models: common core of complex diseases. Sci Rep. 2016;6:27414.

  135. Hu JX, Thomas CE, Brunak S. Network biology concepts in complex disease comorbidities. Nat Rev Genet. 2016;17:615–29.

    Article  CAS  PubMed  Google Scholar 

  136. Cheng Y-R, Jiang B-Y, Chen C-C. Acid-sensing ion channels: dual function proteins for chemo-sensing and mechano-sensing. J Biomed Sci. 2018;25:46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Franze K. The mechanical control of nervous system development. Dev Camb Engl. 2013;140:3069–77.

    CAS  Google Scholar 

  138. Esteva A, Robicquet A, Ramsundar B, Kuleshov V, DePristo M, Chou K, et al. A guide to deep learning in healthcare. Nat Med. 2019;25:24–9.

    Article  CAS  PubMed  Google Scholar 

  139. Min S, Lee B, Yoon S. Deep learning in bioinformatics. Brief Bioinform. 2017;18:851–69.

    PubMed  Google Scholar 

  140. LeCun Y, Bengio Y, Hinton G. Deep learning. Nature. 2015;521:436–44.

    Article  CAS  PubMed  Google Scholar 

  141. Boezio B, Audouze K, Ducrot P, Taboureau O. Network-based Approaches in Pharmacology. Mol Inform. 2017;36(10)

    Article  CAS  Google Scholar 

  142. Ye H, Wei J, Tang K, Feuers R, Hong H. Drug repositioning through network pharmacology. Curr Top Med Chem. 2016;16:3646–56.

    Article  CAS  PubMed  Google Scholar 

  143. Cezar CA, Roche ET, Vandenburgh HH, Duda GN, Walsh CJ, Mooney DJ. Biologic-free mechanically induced muscle regeneration. Proc Natl Acad Sci U S A. 2016;113:1534–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Moreau J-F, Pradeu T, Grignolio A, Nardini C, Castiglione F, Tieri P, et al. The emerging role of ECM crosslinking in T cell mobility as a hallmark of immunosenescence in humans. Ageing Res Rev. 2017;35:322–35.

    Article  CAS  PubMed  Google Scholar 

  145. Politis C, Schoenaers J, Jacobs R, Agbaje JO. Wound healing problems in the mouth. Front Physiol. 2016;7:507

  146. Gilliver SC, Ashworth JJ, Ashcroft GS. The hormonal regulation of cutaneous wound healing. Clin Dermatol. 2007;25:56–62.

    Article  PubMed  Google Scholar 

  147. Ousey K, Cutting KF, Rogers AA, Rippon MG. The importance of hydration in wound healing: reinvigorating the clinical perspective. J Wound Care. 2016;25(122):124–30.

    Google Scholar 

  148. Kunin A, Polivka J, Moiseeva N, Golubnitschaja O. “Dry mouth” and “Flammer” syndromes—neglected risks in adolescents and new concepts by predictive, preventive and personalised approach. EPMA J. 2018;9:307–17.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Wright CF, Fitzgerald TW, Jones WD, Clayton S, McRae JF, van Kogelenberg M, et al. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet Lond Engl. 2015;385:1305–14.

    Article  Google Scholar 

  150. Desai KH, Tan CS, Leek JT, Maier RV, Tompkins RG, Storey JD. Inflammation and the Host Response to Injury Large-Scale Collaborative Research Program Dissecting inflammatory complications in critically injured patients by within-patient gene expression changes: a longitudinal clinical genomics study. PLoS Med. 2011;8:e1001093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Biasci D, Lee JC, Noor NM, Pombal DR, Hou M, Lewis N, et al. A blood-based prognostic biomarker in IBD. Gut. 2019;68:1386–95.

    Article  CAS  PubMed  Google Scholar 

  152. Smolen JS, Landewé R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76:960–77.

    Article  PubMed  Google Scholar 

  153. Kugathasan S, Denson LA, Walters TD, Kim M-O, Marigorta UM, Schirmer M, et al. Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study. Lancet Lond Engl. 2017;389:1710–8.

    Article  Google Scholar 

  154. West NR, Hegazy AN, Owens BMJ, Bullers SJ, Linggi B, Buonocore S, et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med. 2017;23:579–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Aterido A, Cañete JD, Tornero J, Blanco F, Fernández-Gutierrez B, Pérez C, et al. A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis. Front Immunol. 2019;10:1459.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Khera AV, Chaffin M, Aragam KG, Haas ME, Roselli C, Choi SH, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018;50:1219–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Karaderi T, Drong AW, Lindgren CM. Insights into the Genetic susceptibility to type 2 diabetes from genome-wide association studies of obesity-related traits. Curr Diab Rep. 2015;15:83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Gibson G. Going to the negative: genomics for optimized medical prescription. Nat Rev Genet. 2019;20:1–2.

    Article  CAS  PubMed  Google Scholar 

  159. Golubnitschaja O. Flammer syndrome: from phenotype to associated pathologies, prediction, prevention and personalisation. Cham: Springer; 2019. ISBN 978-3-030-13550-8

    Book  Google Scholar 

  160. Konieczka K, Ritch R, Traverso CE, Kim DM, Kook MS, Gallino A, et al. Flammer syndrome. EPMA J. 2014;5:11.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Golubnitschaja O, Flammer J. Individualised patient profile: clinical utility of Flammer syndrome phenotype and general lessons for predictive, preventive and personalised medicine. EPMA J. 2018;9:15–20.

    Article  PubMed  PubMed Central  Google Scholar 

  162. Baban B, Golubnitschaja O. The potential relationship between Flammer and Sjögren syndromes: the chime of dysfunction. EPMA J. 2017;8:333–8.

    Article  PubMed  PubMed Central  Google Scholar 

  163. Hu SC-S, Lan C-CE. High-glucose environment disturbs the physiologic functions of keratinocytes: focusing on diabetic wound healing. J Dermatol Sci. 2016;84:121–7.

    Article  CAS  PubMed  Google Scholar 

  164. Qian S, Golubnitschaja O, Zhan X. Chronic inflammation: key player and biomarker-set to predict and prevent cancer development and progression based on individualized patient profiles. EPMA J. 2019. https://doi.org/10.1007/s13167-019-00194-x.

    Article  Google Scholar 

  165. Bottsford-Miller JN, Taylor M, Dalton HJ, Stone RL, Nick AM, Davis AN, et al. Wound healing gone awry: role for platelets in tumor growth after antiangiogenic therapy. Gynecol Oncol. 2014;133:19.

    Article  Google Scholar 

  166. Koopman FA, van Maanen MA, Vervoordeldonk MJ, Tak PP. Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis. J Intern Med. 2017;282:64–75.

    Article  CAS  PubMed  Google Scholar 

  167. Lerman I, Hauger R, Sorkin L, Proudfoot J, Davis B, Huang A, et al. Noninvasive transcutaneous vagus nerve stimulation decreases whole blood culture-derived cytokines and chemokines: a randomized, blinded, healthy control pilot trial. Neuromodulation. 2016;19:283–90.

    Article  PubMed  Google Scholar 

  168. Bonaz B, Sinniger V, Hoffmann D, Clarençon D, Mathieu N, Dantzer C, et al. Chronic vagus nerve stimulation in Crohn’s disease: a 6-month follow-up pilot study. Neurogastroenterol Motil. 2016;28:948–53.

    Article  CAS  PubMed  Google Scholar 

  169. Wang D-W, Yin Y-M, Yao Y-M. Vagal modulation of the inflammatory response in sepsis. Int Rev Immunol. 2016;35:415–33.

    Article  CAS  PubMed  Google Scholar 

  170. Inoue T, Abe C, Sung SJ, Moscalu S, Jankowski J, Huang L, et al. Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes. J Clin Invest. 2016;126:1939–52.

    Article  PubMed  PubMed Central  Google Scholar 

  171. Park JY, Namgung U. Electroacupuncture therapy in inflammation regulation: current perspectives. J Inflamm Res. 2018;11:227–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Andersson S, Lundeberg T. Acupuncture--from empiricism to science: functional background to acupuncture effects in pain and disease. Med Hypotheses. 1995;45:271–81.

    Article  CAS  PubMed  Google Scholar 

  173. Langevin HM. Acupuncture, connective tissue, and peripheral sensory modulation. Crit Rev Eukaryot Gene Expr. 2014;24:249–53.

    Article  PubMed  Google Scholar 

  174. Goldman N, Chen M, Fujita T, Xu Q, Peng W, Liu W, et al. Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture. Nat Neurosci; United States. 2010;13:883–8 ISBN 1546-1726 (Electronic) 1097-6256 (Linking).

    Article  CAS  Google Scholar 

  175. Ernst M, Lee MH. Sympathetic effects of manual and electrical acupuncture of the Tsusanli knee point: comparison with the Hoku hand point sympathetic effects. Exp Neurol. 1986;94:1–10.

    Article  CAS  PubMed  Google Scholar 

  176. Jun MH, Kim YM, Kim JU. Modern acupuncture-like stimulation methods: a literature review. Integr Med Res. 2015;4:195–219.

    Article  PubMed  PubMed Central  Google Scholar 

  177. Torres-Rosas R, Yehia G, Pena G, Mishra P, del Rocio Thompson-Bonilla M, Moreno-Eutimio MA, et al. Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nat Med. 2014;20:291–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Nardini C, Devescovi V, Liu Y, Zhou X, Lu Y, Dent JE. Systemic wound healing associated with local sub-cutaneous mechanical stimulation. Sci Rep. 2016;6:39043

  179. Moynes DM, Lucas GH, Beyak MJ, Lomax AE. Effects of inflammation on the innervation of the colon. Toxicol Pathol. 2014;42:111–7.

    Article  PubMed  CAS  Google Scholar 

  180. Saunders PR, Miceli P, Vallance BA, Wang L, Pinto S, Tougas G, et al. Noradrenergic and cholinergic neural pathways mediate stress-induced reactivation of colitis in the rat. Auton Neurosci. 2006;124:56–68.

    Article  CAS  PubMed  Google Scholar 

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Conceptualization, C.N., L.M., G.C.G.; investigation, M.G.M, M.S., G.C.G., L.M., C.N.; resources, C.N., L.M., G.C.G.; writing—original draft preparation, M.G.M, G.C.G., L.M., C.N.; writing—review and editing, G.C.G., L.M., C.N.; visualization, M.S, C.N.

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Correspondence to Christine Nardini.

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Maturo, M.G., Soligo, M., Gibson, G. et al. The greater inflammatory pathway—high clinical potential by innovative predictive, preventive, and personalized medical approach. EPMA Journal 11, 1–16 (2020). https://doi.org/10.1007/s13167-019-00195-w

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