Highlights
- •Temporal gene regulatory programs with emphasis on the “inflammatory secretome.”
- •Sequential waves of leukocytes and antecedent patterns of the chemoattractants.
- •Subcellular localization of differentially expressed genes providing new targets.
- •Unique expression patterns of collagen-encoding genes related to tissue remodeling.
Abstract
Pain is a common but potentially debilitating symptom, often requiring complex management
strategies. To understand the molecular dynamics of peripheral inflammation and nociceptive
pain, we investigated longitudinal changes in behavior, tissue structure, and transcriptomic
profiles in the rat carrageenan-induced peripheral inflammation model. Sequential
changes in the number of differentially expressed genes are consistent with temporal
recruitment of key leukocyte populations, mainly neutrophils and macrophages with
each wave being preceded by upregulation of the cell-specific chemoattractants, Cxcl1 and Cxcl2, and Ccl2 and Ccl7, respectively. We defined 12 temporal gene clusters based on expression pattern.
Within the patterns we extracted genes comprising the inflammatory secretome and others
related to nociceptive tissue remodeling and to sensory perception of pain. Structural
tissue changes, involving upregulation of multiple collagens occurred as soon as 1-hour
postinjection, consistent with inflammatory tissue remodeling. Inflammatory expression
profiling revealed a broad-spectrum, temporally orchestrated molecular and cellular
recruitment process. The results provide numerous potential targets for modulation
of pain and inflammation.
Perspective
This study investigates the highly orchestrated biological response during tissue
inflammation with precise assessment of molecular dynamics at the transcriptional
level. The results identify transcriptional changes that define an evolving inflammatory
state in rats. This study provides foundational data for identifying markers of, and
potential treatments for, inflammation and pain in patients.
Key words
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References
- Differential roles of chemokines CCL2 and CCL7 in monocytosis and leukocyte migration during west Nile virus infection.J Immunol. 2015; 195: 4306-4318
- Sensitization of cutaneous neuronal purinergic receptors contributes to endothelin-1-induced mechanical hypersensitivity.Pain. 2014; 155: 1091-1101
- New perspectives on the endothelin axis in pain.Pharmacol Res. 2011; 63: 532-540
- COMPARTMENTS: Unification and visualization of protein subcellular localization evidence.Database (Oxford). 2014; 2014: bau012
- Identification of a novel spinal nociceptive-motor gate control for Adelta pain stimuli in rats.Elife. 2017; 6 (e23584)
- Targeting toll-like receptor-4 (TLR4)-an emerging therapeutic target for persistent pain states.Pain. 2018; 159: 1908-1915
- Granulocyte-colony stimulating factor (G-CSF)-induced mechanical hyperalgesia in mice: Role for peripheral TNFalpha, IL-1beta and IL-10.Eur J Pharmacol. 2015; 749: 62-72
- Inflammation during skeletal muscle regeneration and tissue remodeling: Application to exercise-induced muscle damage management.Immunol Cell Biol. 2016; 94: 140-145
- Human interferon-inducible 10-kDa protein and human interferon-inducible T cell alpha chemoattractant are allotopic ligands for human CXCR3: Differential binding to receptor states.Mol Pharmacol. 2001; 59: 707-715
- Mast cell and macrophage chemokines CXCL1/CXCL2 control the early stage of neutrophil recruitment during tissue inflammation.Blood. 2013; 121: 4930-4937
- Regenerating CNS myelin: Emerging roles of regulatory T cells and CCN proteins.Neurochem Int. 2019; 130104349
- CXCL1 and CXCL2 inhibit the axon outgrowth in a time- and cell-type-dependent manner in adult rat dorsal root ganglia neurons.Neurochem Res. 2019; 44: 2215-2229
- The economic costs of pain in the United States.J Pain. 2012; 13: 715-724
- The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain.Proc Natl Acad Sci U S A. 2009; 106: 14646-14651
- Local injection of endothelin-1 produces pain-like behavior and excitation of nociceptors in rats.J Neurosci. 2001; 21: 5358-5366
- Molecular signatures of mouse TRPV1-lineage neurons revealed by RNA-Seq transcriptome analysis.J Pain. 2014; 15: 1338-1359
- Sex, the aging immune system, and chronic disease.Cell Immunol. 2015; 294: 102-110
- The prokineticin Bv8 sensitizes cutaneous terminals of female mice to heat.Eur J Pain. 2016; 20: 1326-1334
- Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins.Blood. 1993; 81: 1607-1613
- Extracellular ATP has stimulatory effects on the expression and release of IL-6 via purinergic receptors in normal human epidermal keratinocytes.J Invest Dermatol. 2007; 127: 362-371
- Local injection of a selective endothelin-B receptor agonist inhibits endothelin-1-induced pain-like behavior and excitation of nociceptors in a naloxone-sensitive manner.J Neurosci. 2002; 22: 7788-7796
- Endothelin receptors and pain.J Pain. 2009; 10: 4-28
- Ca2+ waves in keratinocytes are transmitted to sensory neurons: The involvement of extracellular ATP and P2Y2 receptor activation.Biochem J. 2004; 380: 329-338
- Postoperative pain and analgesic responses are similar in male and female Sprague-Dawley rats.Can J Anaesth. 2003; 50: 904-908
- Cellular and molecular actions of CCN2/CTGF and its role under physiological and pathological conditions.Clin Sci (Lond). 2015; 128: 181-196
- RNA-Seq investigations of human post-mortem trigeminal ganglia.Cephalalgia. 2018; 38: 912-932
- Prokineticin 2 upregulation in the peripheral nervous system has a major role in triggering and maintaining neuropathic pain in the chronic constriction injury model.Biomed Res Int. 2015; 2015301292
- Keratinocytes and neutrophils are important sources of proinflammatory molecules in hidradenitis suppurativa.Br J Dermatol. 2016; 174: 514-521
- CCN2 modulates hair follicle cycling in mice.Mol Biol Cell. 2013; 24: 3939-3944
- Involvement of CC chemokine receptor 1 and CCL3 in acute and chronic inflammatory pain in mice.Basic Clin Pharmacol Toxicol. 2016; 119: 32-40
- Adult human vascular endothelial cells express the IL6 gene differentially in response to LPS or IL1.Cell Immunol. 1989; 122: 493-503
- CC chemokine ligand 2 (CCL2) enhances TTX-sensitive sodium channel activity of primary afferent neurons in the complete Freud adjuvant-induced inflammatory pain model.Acta Biochim Biophys Sin (Shanghai). 2018; 50: 1219-1226
- Thermal nociception and TRPV1 function are attenuated in mice lacking the nucleotide receptor P2Y2.Pain. 2008; 138: 484-496
- Keratinocytes mediate innocuous and noxious touch via ATP-P2X4 signaling.Elife. 2018; 7 (e31684)
- Uncovering the cells and circuits of touch in normal and pathological settings.Neuron. 2018; 100: 349-360
- Carrageenan-induced paw edema in the rat and mouse.Methods Mol Biol. 2003; 225: 115-121
- Immune cell gene signatures for profiling the microenvironment of solid tumors.Cancer Immunol Res. 2018; 6: 1388-1400
- In vivo imaging reveals an essential role for neutrophils in leishmaniasis transmitted by sand flies.Science. 2008; 321: 970-974
- Silencing of PTX3 alleviates LPS-induced inflammatory pain by regulating TLR4/NF-kappaB signaling pathway in mice.Biosci Rep. 2020; 40 (BSR20194208)
- CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis.Ann Rheum Dis. 2017; 76: 914-922
- Transcriptional changes in dorsal spinal cord persist after surgical incision despite preemptive analgesia with peripheral resiniferatoxin.Anesthesiology. 2018; 128: 620-635
- LocDB: experimental annotations of localization for Homo sapiens and Arabidopsis thaliana.Nucleic Acids Res. 2011; 39: D230-D234
- Interleukin-6 family cytokines.Cold Spring Harb Perspect Biol. 2018; 10 (a028415)
- Sex differences in neuroimmunity and pain.J Neurosci Res. 2017; 95: 500-508
- Keratinocytes contribute to normal cold and heat sensation.Elife. 2020; 9 (e58625)
- Transcriptomic analyses of genes and tissues in inherited sensory neuropathies.Exp Neurol. 2016; 283: 375-395
- Dynorphin and enkephalin opioid peptides and transcripts in spinal cord and dorsal root ganglion during peripheral inflammatory hyperalgesia and allodynia.J Pain. 2020; 21: 988-1004
- Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain.Nat Med. 2009; 15: 802-807
- CXCL1/CXCR2 signaling in pathological pain: Role in peripheral and central sensitization.Neurobiol Dis. 2017; 105: 109-116
- The year of the rat: The rat genome database at 20: A multi-species knowledgebase and analysis platform.Nucleic Acids Res. 2020; 48: D731-D742
- Spinal matrix metalloproteinase 8 regulates pain after peripheral trauma.J Pain Res. 2019; 12: 1133-1138
- Lifting the veil on the keratinocyte contribution to cutaneous nociception.Protein Cell. 2020; 11: 239-250
- A subcellular map of the human proteome.Science. 2017; 356 (eaal3321)
- Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays.Mol Pain. 2009; 5: 28
- UniProt: The universal protein knowledgebase.Nucleic Acids Res. 2018; 46: 2699
- Epidemiology of pain and relation to psychiatric disorders.Prog Neuropsychopharmacol Biol Psychiatry. 2018; 87: 159-167
- S100A8/A9 in inflammation.Front Immunol. 2018; 9: 1298
- SDF1-CXCR4 signaling contributes to the transition from acute to chronic pain state.Mol Neurobiol. 2017; 54: 2763-2775
- Close association of B2 bradykinin receptors with P2Y2 ATP receptors.J Biochem. 2015; 158: 155-163
- Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins.Nature. 2005; 437: 369-375
- A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1.Proc Natl Acad Sci U S A. 2005; 102: 4536-4541
- Comparison of RNA-seq and microarray-based models for clinical endpoint prediction.Genome Biol. 2015; 16: 133
Article info
Publication history
Published online: November 20, 2020
Accepted:
November 2,
2020
Received in revised form:
October 16,
2020
Received:
July 17,
2020
Footnotes
Funding: This study was supported by the Division of Intramural Research Program of the National Institute of Nursing Research, the Department of Perioperative Medicine, Clinical Center and the National Institutes of Neurological Disorders and Stroke, National Institutes of Health. Supplemental funding was provided the National Center for Complementary and Integrative Health, and from the Office of Behavioral and Social Science Research.
Conflict of interest: The authors have no conflict of interest to declare.
Identification
Copyright
© Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc.
