Plexin-A4–semaphorin 3A signaling is required for Toll-like receptor– and sepsis-induced cytokine storm

Wen, Haitao; Lei, Yu; Eun, So Young; Ting, Jenny P.‐Y.

doi:10.1084/jem.20101138

Cited by 95 publications

(87 citation statements)

References 41 publications

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“…29 This observation is supported by studies in which it was observed that sema3A signaling is impaired in mice lacking functional plexin-A4 or plexin-A1 receptors. [31][32][33][34] In another study it was also found that plexin-A4 receptors transduce sema3A guidance signals that affect the organization of the cytoskeleton at growth cones. Interestingly, in this study it was fond that plexin-A3 also transduces sema3A signals.…”

Section: Plexinsmentioning

confidence: 94%

The role of the semaphorins in cancer

Neufeld

Mumblat

Smolkin

et al. 2016

Cell Adhesion & Migration

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The semaphorins were initially characterized as axon guidance factors, but have subsequently been implicated also in the regulation of immune responses, angiogenesis, organ formation, and a variety of additional physiological and developmental functions. The semaphorin family contains more then 20 genes divided into 7 subfamilies, all of which contain the signature sema domain. The semaphorins transduce signals by binding to receptors belonging to the neuropilin or plexin families. Additional receptors which form complexes with these primary semaphorin receptors are also frequently involved in semaphorin signaling. Recent evidence suggests that semaphorins also fulfill important roles in the etiology of multiple forms of cancer. Some semaphorins have been found to function as bona-fide tumor suppressors and to inhibit tumor progression by various mechanisms while other semaphorins function as inducers and promoters of tumor progression. The semaphorin familyThe semaphorin family members are divided into 8 subclasses of which subclasses 1 and 2 contain invertebrate semaphorins while subclasses 3-7 contain the 22 vertebrate semaphorins. The 8th subclass contains viral semaphorins. In early publications, semaphorins were assigned confusing names. This situation was rectified by the adoption of a unified nomenclature in which sema is followed by the subclass number and by alphabetic designation within the subclass.1 Semaphorins are characterized by the presence of a »500 amino-acids long sema domain located close to their N-termini which is also present in semaphorin receptors of the plexin family, and by a plexin-semaphorin-integrin (PSI) domain located downstream to the sema domain. The sema domain is essential for semaphorin activity and plays a role in the determination of the receptor binding specificity.2 The sema domains of several different semaphorins were characterized by X-ray crystallography revealing a b propeller topology.3-5 Different semaphorin subclasses are characterized by class specific structural motifs. Thus, the vertebrate semaphorins belonging to classes 3, 4 and 7 contain immunoglobulin like domains, class-5 semaphorins contain thrombospondin repeats and class-3 semaphorins contain a basic domain. Class-3 semaphorins are the only vertebrate semaphorins produced as secreted proteins while other vertebrate semaphorins are membrane anchored or trans-membrane proteins that can be further processed into soluble forms by proteolytic cleavage (Fig.

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Section: Plexinsmentioning

confidence: 94%

The role of the semaphorins in cancer

Neufeld

Mumblat

Smolkin

et al. 2016

Cell Adhesion & Migration

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“…Mouse kidney proximal tubular epithelial cells (TKPTS) were grown to confluence using advanced DMEM/F-12 medium containing 5% serum in a six-well plate. On the day of treatment, serum-free advanced DMEM/F-12 medium was added, and cells were treated with 50 ng of LPS with 100 ng/ml of sema3A or vehicle for a period of 4 h. Sema3A dose was based on previous studies in macrophages (34). Supernatant and RNA were isolated at the end of the experiment for quantification of cytokines and chemokine expression.…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies suggest that sema3A contributes to sepsis-induced cytokine storm and TLR signaling (34). This suggested that sema3A might cooperate with TLR4 signaling to induce inflammation and kidney damage in AKI.…”

Section: Sema3a Inactivation Blunts Inflammation and Apoptosis In Resmentioning

confidence: 95%

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Semaphorin 3A inactivation suppresses ischemia-reperfusion-induced inflammation and acute kidney injury

Ranganathan

Jayakumar

Mohamed

et al. 2014

American Journal of Physiology-Renal Physiology

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Ranganathan P, Jayakumar C, Mohamed R, Weintraub NL, Ramesh G. Semaphorin 3A inactivation suppresses ischemia-reperfusion-induced inflammation and acute kidney injury. Am J Physiol Renal Physiol 307: F183-F194, 2014. First published May 14, 2014 doi:10.1152/ajprenal.00177.2014.-Recent studies show that guidance molecules that are known to regulate cell migration during development may also play an important role in adult pathophysiologic states. One such molecule, semaphorin3A (sema3A), is highly expressed after acute kidney injury (AKI) in mice and humans, but its pathophysiological role is unknown. Genetic inactivation of sema3A protected mice from ischemia-reperfusion-induced AKI, improved tissue histology, reduced neutrophil infiltration, prevented epithelial cell apoptosis, and increased cytokine and chemokine excretion in urine. Pharmacological-based inhibition of sema3A receptor binding likewise protected against ischemia-reperfusion-induced AKI. In vitro, sema3A enhanced toll-like receptor 4-mediated inflammation in epithelial cells, macrophages, and dendritic cells. Moreover, administration of sema3A-treated, bone marrow-derived dendritic cells exacerbated kidney injury. Finally, sema3A augmented cisplatininduced apoptosis in kidney epithelial cells in vitro via expression of DFFA-like effector a (cidea). Our data suggest that the guidance molecule sema3A exacerbates AKI via promoting inflammation and epithelial cell apoptosis. acute kidney injury; cisplatin; semaphorin3A ACUTE KIDNEY INJURY (AKI) is a common condition in humans that is complicated by lack of effective therapies or preventative strategies. Although the incidence varies between definitions and populations, the disorder is estimated to occur in 1-9% of hospital inpatients and over 40% of critically ill patients treated for sepsis in the intensive care unit (3,7,(12)(13)(14). The pathogenesis of AKI is complex and multifactorial in nature. Inflammation, tubular epithelial cell apoptosis, and impaired perfusion are prominent features that promote acute tubular necrosis and subsequent progression to end-stage renal failure (5, 9, 24).Guidance cues represent a class of molecules that play a key role in development by directing cells to reach target tissues or organs through attraction or repulsion (1,8,28). Although these molecules are also expressed in adult tissues, their function in adult organs is poorly understood. Semaphorins compromise the largest family of axon guidance cues yet discovered and play a key role in neural development. They are characterized structurally by a conserved ϳ400 amino acid sema domain and classically described as collapsing factors and mediators of axon repulsion, although they may also act as context-dependent chemoattractants (26). Semaphorins are divided into eight classes, with classes 3-7 expressed in vertebrates. Class 3 semaphorins are secreted proteins, classes 4 -6 are transmembranous, and class 7 are membrane-associated via glycosylphosphatidylinositol linkages. Semaphorins have also been shown to ...

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“…Following acute kidney injury induced by transient ischemia or by cisplatin, Sema3A protein expression is upregulated in distal and collecting tubules [17,18]. Under these pathophysiological conditions, infiltrating immune cells are likely to serve as an additional source of Sema3A in the kidney [18,19]. The functional role of Sema3A in ischemia/reperfusion injury in vivo has been assessed by both pharmacological as well as genetic approaches employing mice, which carry a loss-of-function mutation in the Sema3A gene.…”

Section: Semaphorins and Plexins In Acute Kidney Injurymentioning

confidence: 99%

Semaphorins and Plexins in Kidney Disease

Xia

Worzfeld

2016

Nephron

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Semaphorins are soluble or membrane-bound cues, which control multiple aspects of cell-cell communication, differentiation, morphology and function. Most of their effects are mediated by a family of transmembrane receptors called plexins. Semaphorins and plexins have emerged as central regulators of diverse physiological and pathophysiological processes in various organs. This review summarizes the role of semaphorins and plexins in renal pathophysiology and their potential use as biomarkers of kidney disease.

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Plexin-A4–semaphorin 3A signaling is required for Toll-like receptor– and sepsis-induced cytokine storm

Abstract: Plexin-A4 activity is essential for Toll-like receptor–induced signaling, cytokine production, and inflammation in mice.

Cited by 95 publications

References 41 publications

The role of the semaphorins in cancer

The role of the semaphorins in cancer

Semaphorin 3A inactivation suppresses ischemia-reperfusion-induced inflammation and acute kidney injury

Semaphorins and Plexins in Kidney Disease

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