The neurite growth inhibitory effects of soluble TNFα on developing sympathetic neurons are dependent on developmental age

Nolan, Aoife; Collins, Louise; Wyatt, Sean; Gutiérrez, Humberto; O’Keeffe, Gerard W.

doi:10.1016/j.diff.2014.12.006

Cited by 15 publications

(11 citation statements)

References 32 publications

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“…Excessive production of inflammatory cytokines is a major cause of pathophysiology in patients with sepsis, and some of these cytokines [i.e., interleukin-1β and tissue necrosis factor-α (TNF-α)] have been implicated in CNS neurodegeneration ( 46 , 47 ). Sympathetic neurons are known to contain receptors for several cytokines ( 48 – 52 ), and TNF-α in particular has actions during development to promoted apoptosis and inhibit neurite growth ( 49 , 53 ). However, there is no evidence for neurotoxic effects of cytokines on adult sympathetic neurons and some can actually stimulate neurite growth ( 50 – 52 ).…”

Section: Discussionmentioning

confidence: 99%

Loss of Sympathetic Nerves in Spleens from Patients with End Stage Sepsis

et al. 2017

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The spleen is an important site for central regulation of immune function by noradrenergic sympathetic nerves, but little is known about this major region of neuroimmune communication in humans. Experimental studies using animal models have established that sympathetic innervation of the spleen is essential for cholinergic anti-inflammatory responses evoked by vagal nerve stimulation, and clinical studies are evaluating this approach for treating inflammatory diseases. Most data on sympathetic nerves in spleen derive from rodent studies, and this work has established that remodeling of sympathetic innervation can occur during inflammation. However, little is known about the effects of sepsis on spleen innervation. Our primary goals were to (i) localize noradrenergic nerves in human spleen by immunohistochemistry for tyrosine hydroxylase (TH), a specific noradrenergic marker, (ii) determine if nerves occur in close apposition to leukocytes, and (iii) determine if splenic sympathetic innervation is altered in patients who died from end stage sepsis. Staining for vesicular acetylcholine transporter (VAChT) was done to screen for cholinergic nerves. Archived paraffin tissue blocks were used. Control samples were obtained from trauma patients or patients who died after hemorrhagic stroke. TH + nerves were associated with arteries and arterioles in all control spleens, occurring in bundles or as nerve fibers. Individual TH + nerve fibers entered the perivascular region where some appeared in close apposition to leukocytes. In marked contrast, spleens from half of the septic patients lacked TH + nerves fibers and the average abundance of TH + nerves for the septic group was only 16% of that for the control group (control: 0.272 ± 0.060% area, n = 6; sepsis: 0.043 ± 0.026% area, n = 8; P < 0.005). All spleens lacked cholinergic innervation. Our results provide definitive evidence for the distribution of noradrenergic nerves in normal human spleen and the first evidence for direct sympathetic innervation of leukocytes in human spleen. We also provide the first evidence for marked loss of noradrenergic nerves in patients who died from sepsis. Such nerve loss could impair neuroimmunomodulation and may not be limited to the spleen.

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Section: Discussionmentioning

confidence: 99%

Loss of Sympathetic Nerves in Spleens from Patients with End Stage Sepsis

et al. 2017

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“…Furthermore, tumor necrosis factor receptor 1 (TNFR1) can act as a ligand for transmembrane TNF and, by reverse signaling, promote axonal growth of sympathetic neurons at late embryonic and early postnatal stages . Conversely, the soluble form of TNFa can inhibit axonal growth through the activation of nuclear factor kappaB (NF-jB) (Gutierrez and Davies 2011;Nolan et al 2014). The same dual role of TNFa is observed in the development of primary nociceptors (Wheeler et al 2014).…”

Section: Introductionmentioning

confidence: 97%

“…Conversely, the soluble form of TNFα can inhibit axonal growth through the activation of nuclear factor kappaB (NF‐κB) (Gutierrez and Davies ; Nolan et al . ). The same dual role of TNFα is observed in the development of primary nociceptors (Wheeler et al .…”

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confidence: 97%

Fas apoptosis inhibitory molecules: more than death‐receptor antagonists in the nervous system

Planells-Ferrer

Urresti

Coccia

et al. 2016

Journal of Neurochemistry

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The importance of death receptor (DR) signaling in embryonic development and physiological homeostasis is well established, as is the existence of several molecules that modulate DRs function, among them Fas Apoptotis Inhibitory Molecules. Although FAIM1, FAIM2, and FAIM3 inhibit Fas-induced cell death, they are not structurally related, nor do they share expression patterns. Moreover, they inhibit apoptosis through completely different mechanisms. FAIM1 and FAIM2 protect neurons from DR-induced apoptosis and are involved in neurite outgrowth and neuronal plasticity. FAIM1 inhibits Fas ligand-and tumor necrosis factor alpha-induced apoptosis by direct interaction with Fas receptor and through the stabilization of levels of X-linked inhibitor of apoptosis protein, a potent anti-apoptotic protein that inhibits caspases. Low FAIM1 levels are found in Alzheimer's disease, thus sensitizing neurons to tumor necrosis factor alpha and prompting neuronal loss. FAIM2 protects from Fas by direct interaction with Fas receptor, as well as by modulating calcium release at the endoplasmic reticulum through interaction with Bcl-xL. Several studies prove the role of FAIM2 in diseases of the nervous system, such as ischemia, bacterial meningitis, and neuroblastoma. The less characterized member of the FAIM family is FAIM3, which is expressed in tissues of the digestive and urinary tracts, bone marrow and testes, and restricted to the cerebellum in the nervous system. FAIM3 protects against DR-induced apoptosis by inducing the expression of other DRantagonists such as CFLAR or through the interaction with the DR-adaptor protein Fas-associated via death domain. FAIM3 null mouse models reveal this protein as an important mediator of inflammatory autoimmune responses such as those triggered in autoimmune encephalomyelitis. Given the

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“…We tested this prediction using gene expression microarray profiling in dissociated cultures of developing sympathetic neurons derived from the SCG. We chose this neuronal population for three reasons: (1) SCG neuronal cultures offer an experimentally tractable model consisting in >95% neurons from a homogeneous neuronal population, thereby eliminating the confounding influence of highly heterogeneous populations of neurons and glia present in dissociated cultures from other regions of the NS (Orike et al, 2001 ; Glebova and Ginty, 2005 ); (2) These neurons have been shown to respond to tumor necrosis factor alpha (TNF-alpha), a cytokine that negatively regulates axonal growth during early postnatal stages (Twohig et al, 2011 ; Kisiswa et al, 2013 ; Nolan et al, 2014 ), thereby offering an ideal opportunity to experimentally assess the effect of an immune-associated cytokine on the global gene expression of dissociated neurons; and (3) While central and peripheral neural tissues share over 99% of their gene expression profiles (LeDoux et al, 2006 ; Smith et al, 2011 ), the use of peripheral neurons provides an additional opportunity to test whether the observed regulatory clustering of immune related genes extends to both central and peripheral neurons.…”

Section: Resultsmentioning

confidence: 99%

Modular and coordinated expression of immune system regulatory and signaling components in the developing and adult nervous system

Monzón‐Sandoval

Castillo-Morales

Crampton

et al. 2015

Front. Cell. Neurosci.

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During development, the nervous system (NS) is assembled and sculpted through a concerted series of neurodevelopmental events orchestrated by a complex genetic programme. While neural-specific gene expression plays a critical part in this process, in recent years, a number of immune-related signaling and regulatory components have also been shown to play key physiological roles in the developing and adult NS. While the involvement of individual immune-related signaling components in neural functions may reflect their ubiquitous character, it may also reflect a much wider, as yet undescribed, genetic network of immune–related molecules acting as an intrinsic component of the neural-specific regulatory machinery that ultimately shapes the NS. In order to gain insights into the scale and wider functional organization of immune-related genetic networks in the NS, we examined the large scale pattern of expression of these genes in the brain. Our results show a highly significant correlated expression and transcriptional clustering among immune-related genes in the developing and adult brain, and this correlation was the highest in the brain when compared to muscle, liver, kidney and endothelial cells. We experimentally tested the regulatory clustering of immune system (IS) genes by using microarray expression profiling in cultures of dissociated neurons stimulated with the pro-inflammatory cytokine TNF-alpha, and found a highly significant enrichment of immune system-related genes among the resulting differentially expressed genes. Our findings strongly suggest a coherent recruitment of entire immune-related genetic regulatory modules by the neural-specific genetic programme that shapes the NS.

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The neurite growth inhibitory effects of soluble TNFα on developing sympathetic neurons are dependent on developmental age

Cited by 15 publications

References 32 publications

Loss of Sympathetic Nerves in Spleens from Patients with End Stage Sepsis

Loss of Sympathetic Nerves in Spleens from Patients with End Stage Sepsis

Fas apoptosis inhibitory molecules: more than death‐receptor antagonists in the nervous system

Modular and coordinated expression of immune system regulatory and signaling components in the developing and adult nervous system

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