Rit signaling contributes to interferon‐γ‐induced dendritic retraction via p38 mitogen‐activated protein kinase activation

Andres, Douglas A.; Shi, Guangpu; Bruun, Donald A.; Barnhart, Chris; Lein, Pamela J.

doi:10.1111/j.1471-4159.2008.05708.x

Cited by 27 publications

(37 citation statements)

References 91 publications

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“…IL-12 activates STAT4 in T H 1 cells and natural killer cells inducing the expression of IFN-γ (Thierfelder et al, 1996), which reinforces the M1 phenotype in macrophages, and promotes the expression of reactive oxygen intermediates and inflammatory cytokines (Benoit et al, 2008). IFN-γ can also act directly on neurons, activating the p38 MAPK pathway and is reported to induce dendrite spine retraction (Andres et al, 2008; Kim et al, 2002). The observed M1 skew is also consistent with an inflammatory phenotype previously observed in splenic CD4+ T cells in offspring of MIA treated dams, including increased production of IL-17 (Hsiao et al, 2012), and the promotion of T H 17 cells (Mandal et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Maternal immune activation leads to activated inflammatory macrophages in offspring

Onore

Schwartzer

Careaga

et al. 2014

Brain, Behavior, and Immunity

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Several epidemiological studies have shown an association between infection or inflammation during pregnancy and increased risk of autism in the child. In addition, animal models have illustrated that maternal inflammation during gestation can cause autism-relevant behaviors in the offspring; so called maternal immune activation (MIA) models. More recently, permanent changes in T cell cytokine responses were reported in children with autism and in offspring of MIA mice; however, the cytokine responses of other immune cell populations have not been thoroughly investigated in these MIA models. Similar to changes in T cell function, we hypothesized that following MIA, offspring will have long-term changes in macrophage function. To test this theory, we utilized the poly (I:C) MIA mouse model in C57BL/6J mice and examined macrophage cytokine production in adult offspring. Pregnant dams were given either a single injection of 20 mg/kg polyinosinic–polycytidylic acid, poly (I:C), or saline delivered intraperitoneally on gestational day 12.5. When offspring of poly (I:C) treated dams reached 10 weeks of age, femurs were collected and bone marrow-derived macrophages were generated. Cytokine production was measured in bone marrow-derived macrophages incubated for 24 h in either growth media alone, LPS, IL-4/LPS, or IFN-γ/LPS. Following stimulation with LPS alone, or the combination of IFN-γ/LPS, macrophages from offspring of poly (I:C) treated dams produced higher levels of IL-12(p40) (p < 0.04) suggesting an increased M1 polarization. In addition, even without the presence of a polarizing cytokine or LPS stimulus, macrophages from offspring of poly (I:C) treated dams exhibited a higher production of CCL3 (p = 0.05). Moreover, CCL3 levels were further increased when stimulated with LPS, or polarized with either IL-4/LPS or IFN-γ/LPS (p < 0.05) suggesting a general increase in production of this chemokine. Collectively, these data suggest that MIA can produce lasting changes in macrophage function that are sustained into adulthood.

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Section: Discussionmentioning

confidence: 99%

Maternal immune activation leads to activated inflammatory macrophages in offspring

Onore

Schwartzer

Careaga

et al. 2014

Brain, Behavior, and Immunity

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“…However, earlier studies have established a role for Rit-dependent p38 signaling in NGF-and PACAP38-mediated pheochromocytoma cell differentiation (27,29) and IFN-␥-mediated dendritic retraction (1). The identification of a general regulatory link between Rit and p38 MAP kinase activation suggests that Rit may be involved in the regulation of additional p38-dependent signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Extensive studies using ectopic expression of active and dominant-negative mutants and RNA interference (RNAi)-based gene silencing approaches have identified roles for Rit signaling in the regulation of neuronal morphogenesis (1,17) and differentiation (27)(28)(29)(30). In addition, overexpression of active Rit has been found to inhibit growth factor withdrawal-mediated apoptosis in pheochromocytoma cells (30), although questions concerning the mechanism of Rit-mediated cell survival signaling remain.…”

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confidence: 99%

A Rit GTPase-p38 Mitogen-Activated Protein Kinase Survival Pathway Confers Resistance to Cellular Stress

Shi

Jin

Andres

2011

Molecular and Cellular Biology

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Cells mobilize diverse signaling cascades to protect against stress-mediated injury. Ras family GTPases play a pivotal role in cell fate determination, serving as molecular switches to control the integration of multiple signaling pathways. p38 mitogen-activated protein kinase (MAPK) signaling serves as a critical fulcrum in this process, regulating networks that stimulate cellular apoptosis but also have the capacity to promote cell survival. However, relatively little is known concerning this functional dichotomy, particularly the regulation of p38-dependent survival pathways. Here, we demonstrate that the Rit GTPase promotes cell survival by directing an unexpected p38 MAPK-dependent AKT survival pathway. Following stress exposure, Rit small hairpin RNA interference (shRNAi)-treated cells display increased apoptosis and selective disruption of p38 MAPK signaling, while expression of constitutively activated Rit promotes p38-AKT-dependent cell survival. Rit, but not Ras or Rap GTPases, can associate with, and is critical for, stress-mediated activation of the scaffolded p38-MK2-HSP27-AKT prosurvival signaling complex. Together, our studies establish Rit as a central regulator of a p38 MAPK-dependent signaling cascade that functions as a critical cellular survival mechanism in response to stress.

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“…Therefore, it is possible that CD8 ϩ effector T cells that are generated in CD4-deficient mice mediate early nerve damage, but damage is not sustained due to defective CD8 ϩ T cell memory. CD8 ϩ T cells in latently infected TG produce IFN-␥ and TNF-␣ and release lytic granules containing granzyme B when stimulated directly ex vivo (27), and all of these molecules have been shown to damage neuronal axons (29)(30)(31)(32). Tarsorrhaphy is a procedure widely used in clinics to protect patients from corneal exposure and desiccation, and the procedure itself does not cause pathology when applied to normal eyes of monkeys (18).…”

Section: Discussionmentioning

confidence: 99%

Reversible Nerve Damage and Corneal Pathology in Murine Herpes Simplex Stromal Keratitis

Yun

Rowe

Lathrop

et al. 2014

J Virol

108

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Herpes simplex virus type 1 (HSV-1) shedding from sensory neurons can trigger recurrent bouts of herpes stromal keratitis (HSK), an inflammatory response that leads to progressive corneal scarring and blindness. A mouse model of HSK is often used to delineate immunopathogenic mechanisms and bears many of the characteristics of human disease, but it tends to be more chronic and severe than human HSK. Loss of blink reflex (BR) in human HSK is common and due to a dramatic retraction of corneal sensory nerve termini in the epithelium and the nerve plexus at the epithelial/stromal interface. However, the relationship between loss of BR due to nerve damage and corneal pathology associated with HSK remains largely unexplored. Here, we show a similar retraction of corneal nerves in mice with HSK. Indeed, we show that much of the HSK-associated corneal inflammation in mice is actually attributable to damage to the corneal nerves and accompanying loss of BR and can be prevented or ameliorated by tarsorrhaphy (suturing eyelids closed), a clinical procedure commonly used to prevent corneal exposure and desiccation. In addition, we show that HSK-associated nerve retraction, loss of BR, and severe pathology all are reversible and regulated by CD4 ؉ T cells. Thus, defining immunopathogenic mechanisms of HSK in the mouse model will necessitate distinguishing mechanisms associated with the immunopathologic response to the virus from those associated with loss of corneal sensation. Based on our findings, investigation of a possible contribution of nerve damage and BR loss to human HSK also appears warranted. IMPORTANCEHSK in humans is a potentially blinding disease characterized by recurrent inflammation and progressive scarring triggered by viral release from corneal nerves. Corneal nerve damage is a known component of HSK, but the causes and consequences of HSK-associated nerve damage remain obscure. We show that desiccation of the corneal surface due to nerve damage and associated loss of BR severely exacerbates and prolongs inflammation-induced pathology in mice. Preventing corneal desiccation results in a milder and more transient HSK with variable scarring that mirrors HSK seen in most humans. We further show that nerve damage is reversible and regulated by CD4 ؉ T cells. Thus, we provide a mouse model that more closely resembles typical human HSK and suggest nerve damage is an important but largely overlooked factor in human disease.

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Rit signaling contributes to interferon‐γ‐induced dendritic retraction via p38 mitogen‐activated protein kinase activation

Cited by 27 publications

References 91 publications

Maternal immune activation leads to activated inflammatory macrophages in offspring

Maternal immune activation leads to activated inflammatory macrophages in offspring

A Rit GTPase-p38 Mitogen-Activated Protein Kinase Survival Pathway Confers Resistance to Cellular Stress

Reversible Nerve Damage and Corneal Pathology in Murine Herpes Simplex Stromal Keratitis

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