TLR 2 and 4 responsiveness from isolated peripheral blood mononuclear cells from rats and humans as potential chronic pain biomarkers

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dc.contributor.authorKwok, Y.
dc.contributor.authorTuke, S.
dc.contributor.authorNicotra, L.
dc.contributor.authorGrace, P.
dc.contributor.authorRolan, P.
dc.contributor.authorHutchinson, M.
dc.contributor.editorPrice, T.J.
dc.date.issued2013
dc.description.abstractBackground: Chronic pain patients have increased peripheral blood mononuclear cell Interkeukin-1β production following TLR2 and TLR4 simulation. Here we have used a human-to-rat and rat-to-human approach to further investigate whether peripheral blood immune responses to TLR agonists might be suitable for development as possible systems biomarkers of chronic pain in humans. Methods and Results: Study 1: using a graded model of chronic constriction injury in rats, behavioral allodynia was assessed followed by in vitro quantification of TLR2 and TLR4 agonist-induced stimulation of IL-1β release by PBMCs and spinal cord tissues (n = 42; 6 rats per group). Statistical models were subsequently developed using the IL-1β responses, which distinguished the pain/no pain states and predicted the degree of allodynia. Study 2: the rat-derived statistical models were tested to assess their predictive utility in determining the pain status of a published human cohort that consists of a heterogeneous clinical pain population (n = 19) and a pain-free population (n = 11). The predictive ability of one of the rat models was able to distinguish pain patients from controls with a ROC AUC of 0.94. The rat model was used to predict the presence of pain in a new chronic pain cohort and was able to accurately predict the presence of pain in 28 out of the 34 chronic pain participants. Conclusions: These clinical findings confirm our previous discoveries of the involvement of the peripheral immune system in chronic pain. Given that these findings are reflected in the prospective graded rat data, it suggests that the TLR response from peripheral blood and spinal cord were related to pain and these clinical findings do indeed act as system biomarkers for the chronic pain state. Hence, they provide additional impetus to the neuroimmune interaction to be a drug target for chronic pain.
dc.description.statementofresponsibilityYuen H. Kwok, Jonathan Tuke, Lauren L. Nicotra, Peter M. Grace, Paul E. Rolan, Mark R. Hutchinson
dc.identifier.citationPLoS One, 2013; 8(10):1-16
dc.identifier.doi10.1371/journal.pone.0077799
dc.identifier.issn1932-6203
dc.identifier.issn1932-6203
dc.identifier.orcidTuke, S. [0000-0002-1688-8951]
dc.identifier.orcidGrace, P. [0000-0002-8999-1220]
dc.identifier.orcidHutchinson, M. [0000-0003-2154-5950]
dc.identifier.urihttp://hdl.handle.net/2440/81863
dc.language.isoen
dc.publisherPublic Library of Science
dc.relation.granthttp://purl.org/au-research/grants/arc/DP110100297
dc.rights© 2013 Kwok et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.source.urihttps://doi.org/10.1371/journal.pone.0077799
dc.subjectSpinal Cord
dc.subjectLeukocytes, Mononuclear
dc.subjectAnimals
dc.subjectHumans
dc.subjectRats
dc.subjectRats, Sprague-Dawley
dc.subjectHyperalgesia
dc.subjectDisease Models, Animal
dc.subjectPain Measurement
dc.subjectPrognosis
dc.subjectCohort Studies
dc.subjectFollow-Up Studies
dc.subjectBehavior, Animal
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectToll-Like Receptor 2
dc.subjectToll-Like Receptor 4
dc.subjectInterleukin-1beta
dc.subjectChronic Pain
dc.subjectBiomarkers
dc.titleTLR 2 and 4 responsiveness from isolated peripheral blood mononuclear cells from rats and humans as potential chronic pain biomarkers
dc.typeJournal article
pubs.publication-statusPublished

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