Inflammatory 'double hit' model of temporomandibular joint disorder with elevated CCL2, CXCL9, CXCL10, RANTES and behavioural hypersensitivity in TNFR1/R2-/- mice.
Patients with temporomandibular joint disorders (TMD), reactive arthritis and rheumatoid arthritis often have combined etiology of hereditary and microenvironmental factors contributing to joint pain. Multiple clinical and animal studies indicate 'double-hit' inflammatory insults can cause chronic inflammation. The first inflammatory insult primes the immune system and subsequent insults elicit amplified responses. The present 'double hit' study produced a chronic orofacial pain model in mice with genetic deletion of both TNFα receptors (TNFR1/R2-/-), investigating the main nociceptive signalling pathways in comparisons to wild type mice.



An initial inflammatory insult was given unilaterally into the temporomandibular joint (TMJ). Secondary hypersensitivity was tested on the skin over the TMJ throughout the experiment. Three weeks later after complete reversal of hypersensitivity, a second inflammatory insult was imposed on the colon. Pharmacological interventions were tested for efficacy after week 10 when hypersensitivity was chronic in TNFR1/R2-/- mice. Serum cytokines were analysed at Days 1, 14, and Week 18.



The double hit insult produced chronic hypersensitivity continuing through the 4-month experimental timeline in the absence of TNFα signalling. P2X7 and NMDA receptor antagonists temporarily attenuated chronic hypersensitivity. Serum cytokine/chemokine analysis on Day 14 when CFA induced hypersensitivity was resolved identified increased levels of pro-inflammatory cytokines CCL2, CXCL9, CXCL10, RANTES and decreased levels of anti-inflammatory cytokines IL-1ra and IL-4 in TNFR1/R2-/- compared to WT mice.



These data suggest a causal feed-forward signalling cascade of these little studied cytokines have the potential to cause recrudescence in this orofacial inflammatory pain model in the absence of TNFα signalling.



Using a mouse model of chronic inflammatory temporomandibular joint disorder, we determined that absence of functional TNFR1/R2 induces aberrant inflammatory signalling caused by other increased pro-inflammatory and decreased anti-inflammatory cytokines that could serve as blood biomarkers and may predict disease progression.
Department of Physiology, College of Medicine, University of Kentucky, Lexington, USA.
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McIlwrath
Department of Physiology, College of Medicine, University of Kentucky, Lexington, USA.
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Nesemeier
Department of Physiology, College of Medicine, University of Kentucky, Lexington, USA.
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Ma
Department of Physiology, College of Medicine, University of Kentucky, Lexington, USA.
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Oz
Department of Physiology, College of Medicine, University of Kentucky, Lexington, USA.
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Zhang
Department of Physiology, College of Medicine, University of Kentucky, Lexington, USA.
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Westlund
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018946:Chemokine CCL5; D054370:Chemokine CXCL9 / Q000378:metabolism*; D018925:Chemokines / Q000737:chemistry* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005157:Facial Pain / Q000378:metabolism*; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry* / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry* / Q000378:metabolism; D013704:Temporomandibular Joint / Q000378:metabolism*; D013705:Temporomandibular Joint Disorders / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; C483024:CCL5 protein, human; C080810:CXCL9 protein, human; D018946:Chemokine CCL5; D054370:Chemokine CXCL9; D018925:Chemokines; D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C439524:TNF protein, human; C506235:TNFRSF1A protein, human; D014409:Tumor Necrosis Factor-alpha