RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways

Rong, Ling; Yan, Shi‐Fang; Wendt, Thoralf; Hans, Diana; Pachydaki, Sophia I.; Bucciarelli, Loredana; Adebayo, Adebukola; Qu, Wu; Lu, Yan; Kostov, Konstantin; Lalla, Evanthia; Yan, Shi Du; Gooch, Clifton L.; Szabolcs, Matthias; Trojaborg, W.; Hays, Arthur P.; Schmidt, Ann Marie

doi:10.1096/fj.04-1900com

Cited by 128 publications

(113 citation statements)

References 28 publications

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“…4). A similar role for RAGE in mediating HMGB1 functional activities has been demonstrated in different models, including regeneration of peripheral nerves [38,62] and tumor growth/metastasis [63].…”

Section: Discussionmentioning

confidence: 53%

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

et al. 2005

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Dendritic cells (DC) are key components of innate and adaptive immune responses. Plasmacytoid DC (PDC) are a specialized DC subset that produce high amounts of type I interferons in response to microbes. High mobility group box 1 protein (HMGB1) is an abundant nuclear protein, which acts as a potent pro-inflammatory factor when released extracellularly. We show that HMGB1 leaves the nucleus of maturing PDC following TLR9 activation, and that PDC express on the plasma membrane the bestcharacterized receptor for HMGB1, RAGE. Maturation and type I IFN secretion of PDC is hindered when the HMGB1/RAGE pathway is disrupted. These results reveal HMGB1 and RAGE as the first known autocrine loop modulating the maturation of PDC, and suggest that antagonists of HMGB1/RAGE might have therapeutic potential for the treatment of systemic human diseases. IntroductionDendritic cells (DC) are potent antigen-presenting cells bridging the innate and adaptive immune responses. To date, two subsets of DC have been identified in humans: myeloid DC and plasmacytoid DC (PDC), the latter also referred to as type I interferon (IFN-a)-producing cells [1][2][3][4][5][6]. PDC recognize viral or bacterial DNA patterns, consisting of unmethylated CpG motifs in the context of species-dependent surrounding sequences (CpG) [7]. As a consequence they produce, within a few hours, large amounts of . Based on their ability to induce IFN-a secretion by PDC, two types of CpG have been described: CpG 2216 (CpG-A), which induces high amounts of IFN-a, and CpG 2006 (CpG-B), which promotes survival, maturation and migration of PDC to the lymph nodes, but induces lower amounts of . PDC sustain the priming of naive T cells and their differentiation into Th1/Th2 effectors [15][16][17] or into regulatory T cells [16,[18][19][20][21][22].Recent studies shed light on the events involved in the recognition of microbial DNA by human PDC, the only subset of human DC that expresses the Toll-like receptor 9 (TLR9) [12]. Both CpG-A and CpG-B have been shown to activate PDC via TLR9 [23]. Upon phagocytosis PDC lyse microorganisms in phagolysosomes, where microbial DNA interacts with and activates TLR9 derived from the endoplasmic reticulum [24]. TLR9 activation leads to recruitment of the MyD88 adaptor protein and phosphorylation of the IL-1R-associated kinase (IRAK). Phosphorylated IRAK associates with the adaptor molecule TNF-associated factor 6 (TRAF6) [25]. Two separate signaling pathways, JNK and NF-jB, are then activated, promoting PDC maturation and survival. IFN-a induction, an event exclusively occurring in PDC, depends on the formation of a complex consisting of MyD88, TRAF6 and the IRF7 transcription factor, as well as on TRAF6-dependent ubiquitination [26].The events that determine the outcome of the interaction of PDC with T cells, and in particular the induction of effector or regulatory immune responses, are poorly characterized. Environmental signals that Here we report that HMGB1 is exported from the nucleus of PDC upon selective engagement of TLR9 an...

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Section: Discussionmentioning

confidence: 53%

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

et al. 2005

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“…To dissect the potential role of mononuclear phagocyte RAGE signaling in modulating the response to diabetes and I/R in the heart, we previously prepared Tg mice expressing DN RAGE selectively in cells of mononuclear phagocyte lineage using the scavenger receptor type A promoter (referred to as MSR DN RAGE) (22). DN RAGE was selectively expressed in mononuclear phagocyte, and there was no evidence that transgene expression was extended outside of monocytes/macrophages (22). Consequent to ischemia, significantly higher iNOS antigen was expressed in the diabetic wild-type heart versus Tg DN MSR Tg DN MSR RAGE heart (P Ͻ 0.05; Fig.…”

Section: Resultsmentioning

confidence: 94%

“…Male RAGE-KO and littermate mice were used. In other studies, two sets of transgenic mice were prepared to express signal transductiondeficient RAGE, or dominant-negative (DN) RAGE (11,12,18) (20,22). Mice were backcrossed Ͼ10 generations into C57BL/6 before the study.…”

Section: Methodsmentioning

confidence: 99%

RAGE and Modulation of Ischemic Injury in the Diabetic Myocardium

et al. 2008

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OBJECTIVE-Subjects with diabetes experience an increased risk of myocardial infarction and cardiac failure compared with nondiabetic age-matched individuals. The receptor for advanced glycation end products (RAGE) is upregulated in diabetic tissues.In this study, we tested the hypothesis that RAGE affected ischemia/reperfusion (I/R) injury in the diabetic myocardium. In diabetic rat hearts, expression of RAGE and its ligands was enhanced and localized particularly to both endothelial cells and mononuclear phagocytes.RESEARCH DESIGN AND METHODS-To specifically dissect the impact of RAGE, homozygous RAGE-null mice and transgenic (Tg) mice expressing cytoplasmic domain-deleted RAGE (DN RAGE), in which RAGE-dependent signal transduction was deficient in endothelial cells or mononuclear phagocytes, were rendered diabetic with streptozotocin. Isolated perfused hearts were subjected to I/R. RESULTS-Diabetic RAGE-null mice were significantly protected from the adverse impact of I/R injury in the heart, as indicated by decreased release of LDH and lower glycoxidation products carboxymethyl-lysine (CML) and pentosidine, improved functional recovery, and increased ATP. In diabetic Tg mice expressing DN RAGE in endothelial cells or mononuclear phagocytes, markers of ischemic injury and CML were significantly reduced, and levels of ATP were increased in heart tissue compared with littermate diabetic controls. Furthermore, key markers of apoptosis, caspase-3 activity and cytochrome c release, were reduced in the hearts of diabetic RAGE-modified mice compared with wild-type diabetic littermates in I/R.CONCLUSIONS-These findings demonstrate novel and key roles for RAGE in I/R injury in the diabetic heart. Diabetes 57: [1941][1942][1943][1944][1945][1946][1947][1948][1949][1950][1951] 2008 C ardiac complications remain a leading cause of morbidity and mortality in subjects with diabetes (1-3). Although many factors contribute to depressed cardiac function in diabetes, innate disturbances within the diabetic heart contribute importantly to progressive dysfunction, which often leads to irreversible failure and death (3). Alterations in substrate metabolism and increased levels of oxygen free radicals have been observed in diabetic tissues. Inflammatory cytokines may exert direct negative inotropic effects on cardiac myocytes and contribute to aberrant remodeling in the failed heart (4 -8). The pathophysiology of diabetesassociated cardiac complications is complex and involves a host of factors linked to metabolic and immune/inflammatory cell activation.The accumulation of late-stage glycoxidation adducts of proteins, termed advanced glycation end products (AGEs), occurs in diabetic tissues. AGEs modify long-lived molecules in the blood vessel wall and structural tissues of the heart considerably earlier than symptomatic cardiac dysfunction occurs (9). A major way in which AGEs exert their cellular effects is by ligation of the multiligand receptor for AGE (RAGE) (10 -13).We tested the role of RAGE in rodent models of type 1 dia...

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“…By using surface plasmon resonance analysis, we previously observed direct binding of H3 to RAGE (10). Importantly, pharmacological blockade of RAGE or the expression of its signal transduction-deficient version impairs restoration of the motor function after sciatic nerve crush (44), making this receptor a possible mediator of the biological effects of H3 in the peripheral nerve.…”

Section: Discussionmentioning

confidence: 99%

Peptide Mimetic of the S100A4 Protein Modulates Peripheral Nerve Regeneration and Attenuates the Progression of Neuropathy in Myelin Protein P0 Null Mice

Moldovan

Pinchenko

Dmytriyeva

et al. 2013

Mol Med

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We recently found that S100A4, a member of the multifunctional S100 protein family, protects neurons in the injured brain and identified two sequence motifs in S100A4 mediating its neurotrophic effect. Synthetic peptides encompassing these motifs stimulated neuritogenesis and survival in vitro and mimicked the S100A4-induced neuroprotection in brain trauma. Here, we investigated a possible function of S100A4 and its mimetics in the pathologies of the peripheral nervous system (PNS). We found that S100A4 was expressed in the injured PNS and that its peptide mimetic (H3) affected the regeneration and survival of myelinated axons. H3 accelerated electrophysiological, behavioral and morphological recovery after sciatic nerve crush while transiently delaying regeneration after sciatic nerve transection and repair. On the basis of the finding that both S100A4 and H3 increased neurite branching in vitro, these effects were attributed to the modulatory effect of H3 on initial axonal sprouting. In contrast to the modest effect of H3 on the time course of regeneration, H3 had a long-term neuroprotective effect in the myelin protein P0 nul mice, a model of dysmyelinating neuropathy (Charcot-Marie-Tooth type 1 disease), where the peptide attenuated the deterioration of nerve conduction, demyelination and axonal loss. From these results, S100A4 mimetics emerge as a possible means to enhance axonal sprouting and survival, especially in the context of demyelinating neuropathies with secondary axonal loss, such as Charcot-Marie-Tooth type 1 disease. Moreover, our data suggest that S100A4 is a neuroprotectant in PNS and that other S10C proteins, sharing high homology in the H3 motif, may have important functions in PNS pathologies.

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RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways

Cited by 128 publications

References 28 publications

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

RAGE and Modulation of Ischemic Injury in the Diabetic Myocardium

Peptide Mimetic of the S100A4 Protein Modulates Peripheral Nerve Regeneration and Attenuates the Progression of Neuropathy in Myelin Protein P0 Null Mice

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