Dataset Information

Neuraxial TNF and IFN-beta co-modulate persistent allodynia in arthritic mice.

ABSTRACT: In rheumatoid arthritis, joint pain can persist despite resolution of swelling. Similarly, in the murine K/BxN serum transfer model, a persistent tactile allodynia is observed after the resolution of joint inflammation (post-inflammatory pain) in male mice. Here, we found female wild type (WT) mice show inflammatory, but reduced post-inflammatory tactile allodynia. The transition to the post-inflammatory phenotype is dependent on TLR4 signaling. At the spinal level, we found differences in TNF and IFN? mRNA expression in WT and TLR4 deficient males. In wild type male and female mice, there is differential temporal spinal expression of TNF and IFN?. In WT males, blockade of TNF or administration of IFN? was insufficient to affect the persistent allodynia. However, co-administration of intrathecal (IT) IFN? and anti-TNF antibodies in male WT mice permanently reversed tactile allodynia. IT IFN? treatment induces expression of anti-inflammatory proteins, contributing to the beneficial effect. Together, these experiments illustrated differences in the transition to chronic tactile allodynia in male and female animals and the complexities of effective pharmacologic interventions.

SUBMITTER: Woller SA

PROVIDER: S-EPMC6396982 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Neuraxial TNF and IFN-beta co-modulate persistent allodynia in arthritic mice.

Woller Sarah A SA Ocheltree Cody C Wong Stephanie Y SY Bui Anthony A Fujita Yuya Y Gonçalves Dos Santos Gilson G Yaksh Tony L TL Corr Maripat M

Brain, behavior, and immunity 20181119

In rheumatoid arthritis, joint pain can persist despite resolution of swelling. Similarly, in the murine K/BxN serum transfer model, a persistent tactile allodynia is observed after the resolution of joint inflammation (post-inflammatory pain) in male mice. Here, we found female wild type (WT) mice show inflammatory, but reduced post-inflammatory tactile allodynia. The transition to the post-inflammatory phenotype is dependent on TLR4 signaling. At the spinal level, we found differences in TNF a ...[more]

PMID: 30465880

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Project description:INTRODUCTION:Rheumatoid arthritis (RA) is a chronic autoimmune disease with episodic flares in affected joints. However, how arthritic flare occurs only in select joints during a systemic autoimmune disease remains an enigma. To better understand these observations, we developed longitudinal imaging outcomes of synovitis and lymphatic flow in mouse models of RA, and identified that asymmetric knee flare is associated with ipsilateral popliteal lymph node (PLN) collapse and the translocation of CD23(+)/CD21(hi) B-cells (B-in) into the paracortical sinus space of the node. In order to understand the relationship between this B-in translocation and lymph drainage from flaring joints, we tested the hypothesis that asymmetric tumor necrosis factor (TNF)-induced knee arthritis is associated with ipsilateral PLN and iliac lymph node (ILN) collapse, B-in translocation, and decreased afferent lymphatic flow. METHODS:TNF transgenic (Tg) mice with asymmetric knee arthritis were identified by contrast-enhanced (CE) magnetic resonance imaging (MRI), and PLN were phenotyped as "expanding" or "collapsed" using LNcap threshold = 30 (Arbitrary Unit (AU)). Inflammatory-erosive arthritis was confirmed by histology. Afferent lymphatic flow to PLN and ILN was quantified by near infrared imaging of injected indocyanine green (NIR-ICG). The B-in population in PLN and ILN was assessed by immunohistochemistry (IHC) and flow cytometry. Linear regression analyses of ipsilateral knee synovial volume and afferent lymphatic flow to PLN and ILN were performed. RESULTS:Afferent lymph flow to collapsed nodes was significantly lower (P < 0.05) than flow to expanding nodes by NIR-ICG imaging, and this occurred ipsilaterally. While both collapsed and expanding PLN and ILN had a significant increase (P < 0.05) of B-in compared to wild type (WT) and pre-arthritic TNF-Tg nodes, B-in of expanding lymph nodes (LN) resided in follicular areas while B-in of collapsed LN were present within LYVE-1+ lymphatic vessels. A significant correlation (P < 0.002) was noted in afferent lymphatic flow between ipsilateral PLN and ILN during knee synovitis. CONCLUSIONS:Asymmetric knee arthritis in TNF-Tg mice occurs simultaneously with ipsilateral PLN and ILN collapse. This is likely due to translocation of the expanded B-in population to the lumen of the lymphatic vessels, resulting in a dramatic decrease in afferent lymphatic flow. PLN collapse phenotype can serve as a new biomarker of knee flare.

Dataset Information

Neuraxial TNF and IFN-beta co-modulate persistent allodynia in arthritic mice.

Publications

Neuraxial TNF and IFN-beta co-modulate persistent allodynia in arthritic mice.

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