RESUMEN
ABSTRACT: Recent evidence highlights the importance of the neuroimmune interface, including periphery-to-central nervous system (CNS) neuroimmune crosstalk, in chronic pain. Although neuroinflammatory processes have been implicated in central sensitization for a long time, their potential neuroprotective and analgesic effects remain relatively elusive. We have explored the relationships between cytokine expression and symptom severity, and candidates for periphery-to-CNS crosstalk. Patients with degenerative disk disease (DDD) (nociceptive pain) or patients with lumbar disk herniation (LDH) with radiculopathy (predominantly neuropathic pain) completed questionnaires regarding pain and functional disability, underwent quantitative sensory testing, and provided blood and cerebrospinal fluid (CSF) samples. Proximity extension assay (PEA) was used to measure the levels of 92 inflammatory proteins in the CSF and serum from a total of 160 patients and controls, and CSF/serum albumin quotients was calculated for patients with DDD and patients with LDH. We found signs of neuroimmune activation, in the absence of systemic inflammation. Regarding periphery-to-CNS neuroimmune crosstalk, there were significant associations between several cytokines and albumin quotient, despite the latter being primarily at subclinical levels. The cytokines CCL11, CD5, IL8, and MMP-10 were elevated in the CSF, had positive correlations between CSF and serum levels, and associated in a nonlinear manner with back, but not leg, pain intensity in the LDH, but not the DDD, group. In conclusion, we found evidence for neuroimmune activation in the CNS of both patient groups in the absence of systemic inflammation and signs of a communication between CSF and serum. Complex and disease-specific associations were found between cytokines in CSF and back pain intensity.
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Dolor Crónico , Citocinas , Degeneración del Disco Intervertebral , Desplazamiento del Disco Intervertebral , Humanos , Masculino , Femenino , Citocinas/líquido cefalorraquídeo , Citocinas/sangre , Persona de Mediana Edad , Desplazamiento del Disco Intervertebral/líquido cefalorraquídeo , Desplazamiento del Disco Intervertebral/complicaciones , Desplazamiento del Disco Intervertebral/inmunología , Degeneración del Disco Intervertebral/líquido cefalorraquídeo , Degeneración del Disco Intervertebral/inmunología , Adulto , Dolor Crónico/líquido cefalorraquídeo , Dolor Crónico/inmunología , Dolor Crónico/sangre , Anciano , Vértebras Lumbares , Dimensión del Dolor/métodos , Neuroinmunomodulación/fisiologíaRESUMEN
Joint pain is one of the most debilitating symptoms of rheumatoid arthritis (RA) and patients frequently rate improvements in pain management as their priority. RA is hallmarked by the presence of anti-modified protein autoantibodies (AMPA) against post-translationally modified citrullinated, carbamylated and acetylated proteins. It has been suggested that autoantibody-mediated processes represent distinct mechanisms contributing to pain in RA. In this study, we investigated the pronociceptive properties of monoclonal AMPA 1325:01B09 (B09 mAb) derived from the plasma cell of an RA patient. We found that B09 mAb induces pain-like behavior in mice that is not associated with any visual, histological or transcriptional signs of inflammation in the joints, and not alleviated by non-steroidal anti-inflammatory drugs (NSAIDs). Instead, we found that B09 mAb is retained in dorsal root ganglia (DRG) and alters the expression of several satellite glia cell (SGC), neuron and macrophage-related factors in DRGs. Using mice that lack activating FcγRs, we uncovered that FcγRs are critical for the development of B09-induced pain-like behavior, and partially drive the transcriptional changes in the DRGs. Finally, we observed that B09 mAb binds SGC in vitro and in combination with external stimuli like ATP enhances transcriptional changes and protein release of pronociceptive factors from SGCs. We propose that certain RA antibodies bind epitopes in the DRG, here on SGCs, form immune complexes and activate resident macrophages via FcγR cross-linking. Our work supports the growing notion that autoantibodies can alter nociceptor signaling via mechanisms that are at large independent of local inflammatory processes in the joint.
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Artritis Reumatoide , Autoanticuerpos , Animales , Ratones , Receptores de IgG , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico , DolorRESUMEN
The organic electronic ion pump (OEIP) is an on-demand electrophoretic drug delivery device, that via electronic to ionic signal conversion enables drug delivery without additional pressure or volume changes. The fundamental component of OEIPs is their polyelectrolyte membranes which are shaped into ionic channels that conduct and deliver ionic drugs, with high spatiotemporal resolution. The patterning of these membranes is essential in OEIP devices and is typically achieved using laborious microprocessing techniques. Here, the development of an inkjet printable formulation of polyelectrolyte is reported, based on a custom anionically functionalized hyperbranched polyglycerol (i-AHPG). This polyelectrolyte ink greatly simplifies the fabrication process and is used in the production of free-standing OEIPs on flexible polyimide (PI) substrates. Both i-AHPG and the OEIP devices are characterized, exhibiting favorable iontronic characteristics of charge selectivity and the ability to transport aromatic compounds. Further, the applicability of these technologies is demonstrated by the transport and delivery of the pharmaceutical compound bupivacaine to dorsal root ganglion cells with high spatial precision and effective nerve blocking, highlighting the applicability of these technologies for biomedical scenarios.
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Electrónica , Microtecnología , Polielectrolitos , Sistemas de Liberación de Medicamentos , Iones/metabolismo , Bombas Iónicas , Preparaciones FarmacéuticasRESUMEN
Bacterial infection results in a veritable cascade of host responses, both local and systemic. To study the initial stages of host-pathogen interaction in living tissue we use spatially-temporally controlled in vivo models. Using this approach, we show here that within 4 h of a uropathogenic Escherichia coli (UPEC) infection in the kidney, an IFNγ response is triggered in the spleen. This rapid infection-mediated inter-organ communication was found to be transmitted via nerve signalling. Bacterial expression of the toxin α-hemolysin directly and indirectly activated sensory neurons, which were identified in the basement membrane of renal tubules. Nerve activation was transmitted via the splenic nerve, inducing upregulation of IFNγ in the marginal zones of the spleen that led to increasing concentrations of IFNγ in the circulation. We found that IFNγ modulated the inflammatory signalling generated by renal epithelia cells in response to UPEC infection. This demonstrates a new concept in the host response to kidney infection; the role of nerves in sensing infection and rapidly triggering a systemic response which can modulate inflammation at the site of infection. The interplay between the nervous and immune systems is an exciting, developing field with the appealing prospect of non-pharmaceutical interventions. Our study identifies an important role for systemic neuro-immune communication in modulating inflammation during the very first hours of a local bacterial infection in vivo.
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Infecciones por Escherichia coli/complicaciones , Interacciones Huésped-Patógeno , Inflamación/patología , Interferón gamma/metabolismo , Riñón/microbiología , Neuroinmunomodulación , Bazo/metabolismo , Animales , Células Epiteliales/microbiología , Inflamación/etiología , Inflamación/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Escherichia coli Uropatógena/fisiologíaRESUMEN
Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.
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Anticuerpos Monoclonales/inmunología , Complejo Antígeno-Anticuerpo/metabolismo , Artralgia/inmunología , Artritis Reumatoide/inmunología , Autoanticuerpos/inmunología , Cartílago/inmunología , Neuronas/metabolismo , Animales , Anticuerpos Monoclonales/uso terapéutico , Artralgia/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Autoanticuerpos/uso terapéutico , Conducta Animal/efectos de los fármacos , Proteína de la Matriz Oligomérica del Cartílago/inmunología , Colágeno Tipo II/inmunología , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Receptores de IgG/deficiencia , Receptores de IgG/genéticaRESUMEN
OBJECTIVES: Patients with rheumatoid arthritis (RA) display an increased risk of heart failure independent of traditional cardiovascular risk factors. To elucidate myocardial disease in RA, we have investigated molecular and cellular remodelling of the heart in an established mouse model of RA. METHODS: The collagen antibody-induced arthritis (CAIA) RA mouse model is characterised by joint inflammation and increased inflammatory markers in the serum. We used CAIA mice in the postinflammatory phase that resembles medically controlled RA or RA in remission. Hearts were collected for cardiomyocyte isolation, biochemistry and histology analysis. RESULTS: Hearts from mice subjected to CAIA displayed hypertrophy (heart/body weight, mean±SD: 5.9±0.8vs 5.1±0.7 mg/g, p<0.05), fibrosis and reduced left ventricular fractional shortening compared with control. Cardiomyocytes from CAIA mice showed reduced cytosolic [Ca2+]i transient amplitudes (F/F0, mean±SD: 3.0±1.2vs 3.6±1.5, p<0.05) that was linked to reductions in sarcoplasmic reticulum (SR) Ca2+ store (F/F0, mean±SD: 3.5±1.3vs 4.4±1.3, p<0.01) measured with Ca2+ imaging. This was associated to lower fractional shortening in the cardiomyocytes from the CAIA mice (%FS, mean±SD: 3.4±2.2 vs 4.6%±2.3%, p<0.05). Ca2+ handling proteins displayed oxidation-dependent posttranslational modifications that together with an increase in superoxide dismutase expression indicate a cell environment with oxidative stress. CONCLUSIONS: This study shows that inflammation during active RA has long-term consequences on molecular remodelling and contractile function of the heart, which further supports that rheumatology patients should be followed for development of heart failure.
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Artritis Experimental/complicaciones , Artritis Reumatoide/complicaciones , Cardiomiopatías/etiología , Contracción Miocárdica , Miocitos Cardíacos/metabolismo , Estrés Oxidativo , Función Ventricular Izquierda , Animales , Artritis Experimental/metabolismo , Artritis Experimental/patología , Artritis Experimental/fisiopatología , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Artritis Reumatoide/fisiopatología , Canales de Calcio Tipo L/metabolismo , Señalización del Calcio , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Cardiomiopatías/fisiopatología , Femenino , Fibrosis , Masculino , Ratones Endogámicos BALB C , Miocitos Cardíacos/patología , Procesamiento Proteico-Postraduccional , Retículo Sarcoplasmático/metabolismo , Remodelación VentricularRESUMEN
In this issue of Neuron, Dawes et al. (2018) show that CASPR2 antibodies (Abs) isolated from patients bind specifically to primary afferent cell bodies and induce neuropathic pain in mice. Consequent decreased expression of Kv1 channels and their aberrant localization along myelinated axons explain the observed hyperexcitability and pain.
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Autoanticuerpos , Neuralgia , Animales , Axones , Humanos , Proteínas de la Membrana , Ratones , Proteínas del Tejido NerviosoRESUMEN
OBJECTIVE: An interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation. METHODS: Antibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28â days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin. RESULTS: Mice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin. CONCLUSIONS: The data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation.