Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation

Pan, Yang; Lloyd, Clare M.; Zhou, Hong; Dolich, Sylvia; Deeds, Jim; Gonzalo, José-Ángel; Vath, Jim; Gosselin, Mike; Ma, Jingya; Dussault, Barry J.; Woolf, Elizabeth A.; Alperin, Geoff; Culpepper, Janice; Gutierrez‐Ramos, José Carlos; Gearing, David P.

doi:10.1038/42491

Cited by 600 publications

(489 citation statements)

References 31 publications

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“…Endothelial cells upregulate the expression of both these molecules in response to TNF, IL-1 and LPS [33][34][35][36]40]. In addition, VCAM-1 and fractalkine are expressed in many of the same inflammatory diseases, including murine models of cardiac allograft rejection [19,41,42], crescentric nephritis [20,43] and experimental autoimmune encephalomyelitis [21,22,44]. Blockade of fractalkine-CX 3 CR1 interactions is beneficial in a murine model of crescentric glomerulonephritis [20].…”

Section: Discussionmentioning

confidence: 99%

“…However, it is the membrane-bound form that has generated the most interest as it potentially combines the direct action of an adhesion molecule with the specificity of a chemokine. Membrane-bound fractalkine is highly expressed in a number of murine models of inflammatory disease including cardiac allograft rejection [19], crescentric glomerulonephritis [20], and experimental autoimmune encephalomyelitis [21,22], as well as in the human inflammatory diseases rheumatoid arthritis [23], psoriasis [24] and atherosclerosis [25]. It is therefore very important to understand the mechanisms by which this chemokine may contribute to disease processes.…”

Section: Introductionmentioning

confidence: 99%

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Human fractalkine mediates leukocyte adhesion but not capture under physiological shear conditions; a mechanism for selective monocyte recruitment

et al. 2003

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Fractalkine is a unique chemokine possessing a long mucin-like stalk and a transmembrane region that has been proposed to act as an adhesion molecule. We investigated the ability of fractalkine to recruit leukocytes from whole blood, using an immobilized fractalkine fusion protein in the parallel-plate flow-chamber assay. Significant adhesion of leukocytes to fractalkine peaked at 2 dynes/cm 2 but was minimal at 10 dynes/cm 2 . In contrast, VCAM-1 could recruit cells from whole blood at 10 dynes/cm 2 . Co-immobilization of fractalkine and VCAM-1 at 10 dynes/cm 2 resulted in a twofold increase in adherent cells compared with VCAM-1 alone, suggesting that fractalkine can mediate adhesion at high shear if combined with a molecule that can mediate leukocyte tethering. Pretreatment of blood with pertussis toxin eliminated this increase in adhesion, implicating intracellular signaling in fractalkinemediated mechanisms of adhesion to co-immobilized fractalkine/VCAM-1. Analysis of the cell types recruited to fractalkine alone at low shear, or to fractalkine and VCAM-1 at 10 dynes/cm 2 , revealed that monocytes were recruited to fractalkine with the highest specificity. In conclusion, fractalkine is unlikely to act alone at shear forces found in most vascular beds where it most likely co-operates with tethering molecules, e.g. VCAM-1, in the recruitment of monocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human fractalkine mediates leukocyte adhesion but not capture under physiological shear conditions; a mechanism for selective monocyte recruitment

et al. 2003

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“…Fractalkine is another factor released by neurons of the pain pathway, which has been documented to mediate pathological pain (Clark et al, 2007, Lindia et al, 2005, Milligan et al, 2005c, Zhuang et al, 2007. Fractalkine, first discovered as neurotactin (Pan et al, 1997) is a chemokine, a term which refers to a family of over 50 proteins classically known as chemotactic cytokines (Asensio and Campbell, 1999) that induces leukocyte migration and facilitates inflammation (Thomson and Lotze, 2003). While chemokines typically bind multiple receptors and conversely, chemokine receptors bind multiple chemokines, this does not hold true for fractalkine (Rostene et al, 2007).…”

Section: Neuron-to-glia Signals: Fractalkinementioning

confidence: 99%

Glia in pathological pain: A role for fractalkine

Milligan

Sloane

Watkins

2008

Journal of Neuroimmunology

104

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Microglia and/or astrocytes play a significant role in the creation and maintenance of exaggerated pain states with inflammatory and/or neuropathic etiologies. The chemokine, fractalkine, has several functions, including the newly recognized role of mediating neuropathic pain conditions. Although constitutively expressed and released during inflammation, increased release of fractalkine binds to and activates microglia glia leading to pathological pain. We review the critical role of fractalkine in neuron-to-glial communication after peripheral nerve injury and inflammation and explore anti-inflammatory cytokines like interleukin-10 as a novel and effective approach for clinical pain control. KeywordsNeuropathic pain; spinal cord; microglia; astrocytes; interleukin-10; gene therapy Previously Understood Views of PainTraditionally, our understanding about neuronal signaling for pain transmission from the body to the central nervous system (CNS) occurs as a series of relay signals that are eventually processed in the brain. These relay signals are thought to serve protective and adaptive roles, with the first synaptic relay, between the first order (sensory) neuron and the second order neuron in the dorsal horn of the spinal cord. Neurons that receive and respond to pain information are primarily located in anatomically discrete regions of the spinal cord, that is, laminae I, II and V of the spinal cord dorsal horns. From the spinal cord dorsal horn, pain projection neurons relay their information to higher pain centers, such as to the brainstem and various relevant pain areas in the brain. Interestingly, the dorsal horn of the spinal cord can strongly modulate pain signaling (Millan, 1999). Although the neuronal functioning of these pain pathways has been examined for decades, the induction and maintenance of non-adaptive, pathological pain is poorly understood. However, since the early 1990's, there has been mounting evidence that glial cells (both astrocytes and microglia), in addition to neurons, also play a critical role in pain modulation (DeLeo et al., 2007).

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“…Regarding the severity of AD, severe AD Patients with AD exhibited elevated sFKN levels that significantly decreased with the improvement of skin lesions by treatment. Since sFKN enhances the chemotactic activity of CX 3 CR1-expressing cells 12,43,44 , sFKN may promote CX 3 CR1 + cell infiltration into the affected tissue. However, recent studies have revealed that sFKN inhibits the adhesion of CX 3 CR1-expressing leukocytes to endothelial cells 12,29,43,44 .…”

Section: Serum Sfkn Levelsmentioning

confidence: 99%

“…Since sFKN enhances the chemotactic activity of CX 3 CR1-expressing cells 12,43,44 , sFKN may promote CX 3 CR1 + cell infiltration into the affected tissue. However, recent studies have revealed that sFKN inhibits the adhesion of CX 3 CR1-expressing leukocytes to endothelial cells 12,29,43,44 . A similar function has been reported in other adhesion molecules including L-selectin 45,46 .…”

Section: Serum Sfkn Levelsmentioning

confidence: 99%