MAPK Phosphotase 5 Deficiency Contributes to Protection against Blood-Stage <i>Plasmodium yoelii</i> 17XL Infection in Mice

Cheng, Qianqian; Zhang, Qingfeng; Xu, Xindong; Yin, Lan; Sun, Limin; Lin, Xin; Dong, Chen; Pan, Weiqing

doi:10.4049/jimmunol.1301863

Cited by 11 publications

(15 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…yoelii 17XNL, we focused on the immune mediators that are essential for resolution of blood-stage malaria. Given that optimal induction of proinflammatory cytokines (e.g., IFN-γ and TNF-α), and the counterbalance exerted by anti-inflammatory cytokines (TGF-β and IL-10) are crucial for determining the outcome of blood-stage malaria [ 16 – 19 ], we first analyzed the serum levels of these molecules. Notably, there was a remarkable elevation of IFN-γ in Uba3 fl/fl mice early after P .…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Neddylation contributes to CD4+ T cell-mediated protective immunity against blood-stage Plasmodium infection

Cheng¹,

Liu²,

Pei³

et al. 2018

PLoS Pathog

Self Cite

View full text Add to dashboard Cite

CD4+ T cells play predominant roles in protective immunity against blood-stage Plasmodium infection, both for IFN-γ-dependent effector mechanisms and providing B cell helper signals. Neddylation, an ubiquitination-like process triggered by covalent conjugation of NEDD8 to specific targets, has emerged as a potential regulator of T cell activities to TCR engagement. However, its contribution to T cell-mediated immunity to blood-stage malaria remains unclear. Here using an experimental model induced by Plasmodium yoelii 17XNL, and conditional knockout mice with T cell-specific deficiency of crucial components of neddylation pathway, we demonstrate activation of neddylation in T cells during blood-stage Plasmodium infection is essential for parasite control and host survival. Mechanistically, we show that apart from promoting CD4+ T cell activation, proliferation, and development of protective T helper 1 (Th1) cell response as suggested previously, neddylation is also required for supporting CD4+ T cell survival, mainly through B-cell lymphoma-2 (Bcl-2) mediated suppression of the mitochondria-dependent apoptosis. Furthermore, we provide evidence that neddylation contributes to follicular helper T (Tfh) cell differentiation, probably via augmenting the ubiquitin ligase Itch activity and proteasomal degradation of FoxO1, thereby facilitating germinal center (GC) formation and parasite-specific antibody production. This study identifies neddylation as a positive regulator of anti-Plasmodium immunity and provides insight into an involvement of such pathway in host resistance to infectious diseases.

show abstract

Section: Resultsmentioning

confidence: 99%

“…The cloned line of blood-stage P . yoelii 17XNL was stored as described [ 16 ]. Infection was initiated by i.p.…”

Section: Methodsmentioning

confidence: 99%

Neddylation contributes to CD4+ T cell-mediated protective immunity against blood-stage Plasmodium infection

Cheng¹,

Liu²,

Pei³

et al. 2018

PLoS Pathog

Self Cite

View full text Add to dashboard Cite

show abstract

“…A selected group of DUSP enzymes display overexpression or hyperactivity that is associated with human disease, especially human cancer, making feasible targeted therapy approaches based on their inhibition. In the past decade, DUSPs were shown to play important roles in regulating immune cell functions in vitro and in vivo [ 35 , 37 – 46 ]. For example, DUSP1 was involved in regulating the production of inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Profiles of Human Lung Epithelial Cells A549 Interacting with Aspergillus fumigatus by RNA-Seq

et al. 2015

View full text Add to dashboard Cite

Lung epithelial cells constitute the first defense line of host against the inhaled Aspergillus fumigatus; however, the transcriptional response of human alveolar type II epithelial cells was still unclear. Here we used RNA-Seq technology to assess the transcriptome profiles of A549 cells following direct interaction with conidia of A. fumigatus. The total number of identified genes was 19118. Compared with uninfected A549 cells, 459 genes were differentially expressed in cells co-incubated with conidia for 8 h, including 302 up-regulated genes and 157 down-regulated genes. GO and KEGG pathway enrichment analysis showed that most of the up-regulated genes were related to immune response, chemotaxis and inflammatory response and enriched in cytokine-cytokine receptor interaction, JAK-STAT and MAPK signaling pathways. The down-regulated genes were mainly enriched for terms associated with development, hemopoiesis and ion transport. Among them, EGR4 and HIST1H4J gene had the maximum of fold change in up-regulated and down-regulated genes, respectively. Fourteen up-regulated genes and three down-regulated genes were further validated and significant increase on expression of IL-6, IL-8 and TNF-α in A549 cells were confirmed by qRT-PCR during the interaction of A549 cells with A. fumigatus. Besides, western blot showed that expression of two proteins (ARC, EGR1) significantly increased in A549 cells during interaction with A. fumigatus conidia for 8h. Interference of endogenous expression of ARC or EGR1 protein in A549 cells reduced the internalization of A. fumigatus. These results provided important insights into dynamic changes of gene expression in lung epithelial cells, especially its strong immunological response against A. fumigatus infection.

show abstract

“…MKP-5 has differential roles in the regulation of T cell clonal expansion and effector T cell cytokine expression, MKP-5 deficient T cells proliferated poorly upon activation which resulted in increased resistance to EAE than the wild type controls16. The emerging research evidence thus suggests that MKPs play important roles in the regulation of inflammatory responses such as sepsis, infection and CNS inflammation23521, and they may become potential therapeutic targets for inflammatory diseases such as MS.…”

Section: Discussionmentioning

confidence: 99%

“…ERK, JNK, p38) via dephosphorylation of phosphotyrosine and phosphothreonine residues, and thus play a key role in inflammation mediated diseases. Indeed various MKPs including MKP-1, MKP-5, MKP-7, MKP-x (DUSP22) and DUSP5 have been shown to be important in regulating immune responses123456. For example, MKP-1 negatively regulates the production of inflammatory cytokines TNF-α, IL-6 and IL-1β, and the anti-inflammatory IL-10789, as well as chemokines and other inflammatory mediators10111213.…”

mentioning

confidence: 99%

MAP kinase phosphatase 2 deficient mice develop attenuated experimental autoimmune encephalomyelitis through regulating dendritic cells and T cells

Barbour

Plevin

Jiang

2016

Sci Rep

View full text Add to dashboard Cite

Mitogen-activated protein kinase phosphatases (MKPs) play key roles in inflammation and immune mediated diseases. Here we investigated the mechanisms by which MKP-2 modulates central nervous system (CNS) inflammation in experimental autoimmune encephalomyelitis (EAE). Our results show that MKP-2 mRNA levels in the spinal cord and lymphoid organs of EAE mice were increased compared with naive controls, indicating an important role for MKP-2 in EAE development. Indeed, MKP-2−/− mice developed reduced EAE severity, associated with diminished CNS immune cell infiltration, decreased proinflammatory cytokine production and reduced frequency of CD4+ and CD8+ T cells in spleens and lymph nodes. In addition, MKP-2−/− CD11c+ dendritic cells (DCs) had reduced expression of MHC-II and CD40 compared with MKP-2+/+ mice. Subsequent experiments revealed that CD4+ T cells from naïve MKP-2−/− mice had decreased cell proliferation and IL-2 and IL-17 production relative to wild type controls. Furthermore, co-culture experiments showed that bone marrow derived DCs of MKP-2−/− mice had impaired capability in antigen presentation and T cell activation. While MKP-2 also modulates macrophage activation, our study suggests that MKP-2 is essential to the pathogenic response of EAE, and it acts mainly via regulating the important antigen presenting DC function and T cell activation.

show abstract

MAPK Phosphotase 5 Deficiency Contributes to Protection against Blood-Stage Plasmodium yoelii 17XL Infection in Mice

Cited by 11 publications

References 61 publications

Neddylation contributes to CD4+ T cell-mediated protective immunity against blood-stage Plasmodium infection

Neddylation contributes to CD4+ T cell-mediated protective immunity against blood-stage Plasmodium infection

Transcriptome Profiles of Human Lung Epithelial Cells A549 Interacting with Aspergillus fumigatus by RNA-Seq

MAP kinase phosphatase 2 deficient mice develop attenuated experimental autoimmune encephalomyelitis through regulating dendritic cells and T cells

Contact Info

Product

Resources

About