Eda Holl

Positions:

Assistant Professor of Surgery

Surgery, Surgical Sciences
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2010

University of North Carolina at Chapel Hill

Grants:

Retrospective Review Evaluating the PSA Changes in Patients with Metastatic Castrate Resistant Prostate Cancer after Sipuleucel-T treatment

Administered By
Duke Cancer Institute
Role
Principal Investigator
Start Date
End Date

Publications:

Plexin-B2 and Plexin-D1 in dendritic cells: expression and IL-12/IL-23p40 production.

Plexins are a family of genes (A,B,C, and D) that are expressed in many organ systems. Plexins expressed in the immune system have been implicated in cell movement and cell-cell interaction during the course of an immune response. In this study, the expression pattern of Plexin-B2 and Plexin-D1 in dendritic cells (DCs), which are central in immune activation, was investigated. Plexin-B2 and Plexin-D1 are reciprocally expressed in myeloid and plasmacytoid DC populations. Plasmacytoid DCs have high Plexin-B2 but low Plexin-D1, while the opposite is true of myeloid DCs. Expression of Plexin-B2 and Plexin-D1 is modulated upon activation of DCs by TLR ligands, TNFα, and anti-CD40, again in a reciprocal fashion. Semaphorin3E, a ligand for Plexin-D1 and Plexin-B2, is expressed by T cells, and interestingly, is dramatically higher on Th2 cells and on DCs. The expression of Plexins and their ligands on DCs and T cells suggest functional relevance. To explore this, we utilized chimeric mice lacking Plxnb2 or Plxnd1. Absence of Plexin-B2 and Plexin-D1 on DCs did not affect the ability of these cells to upregulate costimulatory molecules or the ability of these cells to activate antigen specific T cells. Additionally, Plexin-B2 and Plexin-D1 were dispensable for chemokine-directed in-vitro migration of DCs towards key DC chemokines, CXCL12 and CCL19. However, the absence of either Plexin-B2 or Plexin-D1 on DCs leads to constitutive expression of IL-12/IL-23p40. This is the first report to show an association between Plexin-B2 and Plexin-D1 with the negative regulation of IL-12/IL-23p40 in DCs. This work also shows the presence of Plexin-B2 and Plexin-D1 on mouse DC subpopulations, and indicates that these two proteins play a role in IL-12/IL-23p40 production that is likely to impact the immune response.
Authors
Holl, EK; Roney, KE; Allen, IC; Steinbach, E; Arthur, JC; Buntzman, A; Plevy, S; Frelinger, J; Ting, JP-Y
MLA Citation
Holl, Eda K., et al. “Plexin-B2 and Plexin-D1 in dendritic cells: expression and IL-12/IL-23p40 production..” Plos One, vol. 7, no. 8, 2012. Pubmed, doi:10.1371/journal.pone.0043333.
URI
https://scholars.duke.edu/individual/pub1125449
PMID
22916243
Source
pubmed
Published In
Plos One
Volume
7
Published Date
Start Page
e43333
DOI
10.1371/journal.pone.0043333

Plexin-B2 negatively regulates macrophage motility, Rac, and Cdc42 activation.

Plexins are cell surface receptors widely studied in the nervous system, where they mediate migration and morphogenesis though the Rho family of small GTPases. More recently, plexins have been implicated in immune processes including cell-cell interaction, immune activation, migration, and cytokine production. Plexin-B2 facilitates ligand induced cell guidance and migration in the nervous system, and induces cytoskeletal changes in overexpression assays through RhoGTPase. The function of Plexin-B2 in the immune system is unknown. This report shows that Plexin-B2 is highly expressed on cells of the innate immune system in the mouse, including macrophages, conventional dendritic cells, and plasmacytoid dendritic cells. However, Plexin-B2 does not appear to regulate the production of proinflammatory cytokines, phagocytosis of a variety of targets, or directional migration towards chemoattractants or extracellular matrix in mouse macrophages. Instead, Plxnb2(-/-) macrophages have greater cellular motility than wild type in the unstimulated state that is accompanied by more active, GTP-bound Rac and Cdc42. Additionally, Plxnb2(-/-) macrophages demonstrate faster in vitro wound closure activity. Studies have shown that a closely related family member, Plexin-B1, binds to active Rac and sequesters it from downstream signaling. The interaction of Plexin-B2 with Rac has only been previously confirmed in yeast and bacterial overexpression assays. The data presented here show that Plexin-B2 functions in mouse macrophages as a negative regulator of the GTPases Rac and Cdc42 and as a negative regulator of basal cell motility and wound healing.
Authors
Roney, KE; O'Connor, BP; Wen, H; Holl, EK; Guthrie, EH; Davis, BK; Jones, SW; Jha, S; Sharek, L; Garcia-Mata, R; Bear, JE; Ting, JP-Y
MLA Citation
Roney, Kelly E., et al. “Plexin-B2 negatively regulates macrophage motility, Rac, and Cdc42 activation..” Plos One, vol. 6, no. 9, 2011. Pubmed, doi:10.1371/journal.pone.0024795.
URI
https://scholars.duke.edu/individual/pub1125452
PMID
21966369
Source
pubmed
Published In
Plos One
Volume
6
Published Date
Start Page
e24795
DOI
10.1371/journal.pone.0024795

The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer.

Colitis-associated cancer (CAC) is a major complication of inflammatory bowel diseases. We show that components of the inflammasome are protective during acute and recurring colitis and CAC in the dextran sulfate sodium (DSS) and azoxymethane + DSS models. Mice lacking the inflammasome adaptor protein PYCARD (ASC) and caspase-1 demonstrate increased disease outcome, morbidity, histopathology, and polyp formation. The increased tumor burden is correlated with attenuated levels of IL-1beta and IL-18 at the tumor site. To decipher the nucleotide-binding domain, leucine-rich-repeat-containing (NLR) component that is involved in colitis and CAC, we assessed Nlrp3 and Nlrc4 deficient mice. Nlrp3(-/-) mice showed an increase in acute and recurring colitis and CAC, although the disease outcome was less severe in Nlrp3(-/-) mice than in Pycard(-/-) or Casp1(-/-) animals. No significant differences were observed in disease progression or outcome in Nlrc4(-/-) mice compared with similarly treated wild-type animals. Bone marrow reconstitution experiments show that Nlrp3 gene expression and function in hematopoietic cells, rather than intestinal epithelial cells or stromal cells, is responsible for protection against increased tumorigenesis. These data suggest that the inflammasome functions as an attenuator of colitis and CAC.
Authors
Allen, IC; TeKippe, EM; Woodford, R-MT; Uronis, JM; Holl, EK; Rogers, AB; Herfarth, HH; Jobin, C; Ting, JP-Y
MLA Citation
Allen, Irving C., et al. “The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer..” J Exp Med, vol. 207, no. 5, May 2010, pp. 1045–56. Pubmed, doi:10.1084/jem.20100050.
URI
https://scholars.duke.edu/individual/pub1125448
PMID
20385749
Source
pubmed
Published In
J Exp Med
Volume
207
Published Date
Start Page
1045
End Page
1056
DOI
10.1084/jem.20100050

The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA.

The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) family of pattern-recognition molecules mediate host immunity to various pathogenic stimuli. However, in vivo evidence for the involvement of NLR proteins in viral sensing has not been widely investigated and remains controversial. As a test of the physiologic role of the NLR molecule NLRP3 during RNA viral infection, we explored the in vivo role of NLRP3 inflammasome components during influenza virus infection. Mice lacking Nlrp3, Pycard, or caspase-1, but not Nlrc4, exhibited dramatically increased mortality and a reduced immune response after exposure to the influenza virus. Utilizing analogs of dsRNA (poly(I:C)) and ssRNA (ssRNA40), we demonstrated that an NLRP3-mediated response could be activated by RNA species. Mechanistically, NLRP3 inflammasome activation by the influenza virus was dependent on lysosomal maturation and reactive oxygen species (ROS). Inhibition of ROS induction eliminated IL-1beta production in animals during influenza infection. Together, these data place the NLRP3 inflammasome as an essential component in host defense against influenza infection through the sensing of viral RNA.
Authors
Allen, IC; Scull, MA; Moore, CB; Holl, EK; McElvania-TeKippe, E; Taxman, DJ; Guthrie, EH; Pickles, RJ; Ting, JP-Y
MLA Citation
Allen, Irving C., et al. “The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA..” Immunity, vol. 30, no. 4, Apr. 2009, pp. 556–65. Pubmed, doi:10.1016/j.immuni.2009.02.005.
URI
https://scholars.duke.edu/individual/pub1125447
PMID
19362020
Source
pubmed
Published In
Immunity
Volume
30
Published Date
Start Page
556
End Page
565
DOI
10.1016/j.immuni.2009.02.005

Semaphorin 6D regulates the late phase of CD4+ T cell primary immune responses.

The semaphorin and plexin family of ligand and receptor proteins provides important axon guidance cues required for development. Recent studies have expanded the role of semaphorins and plexins in the regulation of cardiac, circulatory and immune system function. Within the immune system, semaphorins and plexins regulate cell-cell interactions through a complex network of receptor and ligand pairs. Immune cells at different stages of development often express multiple semaphorins and plexins, leading to multivariate interactions, involving more than one ligand and receptor within each functional group. Because of this complexity, the significance of semaphorin and plexin regulation on individual immune cell types has yet to be fully appreciated. In this work, we examined the regulation of T cells by semaphorin 6D. Both in vitro and in vivo T cell stimulation enhanced semaphorin 6D expression. However, semaphorin 6D was only expressed by a majority of T cells during the late phases of activation. Consequently, the targeted disruption of semaphorin 6D receptor-ligand interactions inhibited T cell proliferation at late but not early phases of activation. This proliferation defect was associated with reduced linker of activated T cells protein phosphorylation, which may reflect semaphorin 6D regulation of c-Abl kinase activity. Semaphorin 6D disruption also inhibited expression of CD127, which is required during the multiphase antigen-presenting cell and T cell interactions leading to selection of long-lived lymphocytes. This work reveals a role for semaphorin 6D as a regulator of the late phase of primary immune responses.
Authors
O'Connor, BP; Eun, S-Y; Ye, Z; Zozulya, AL; Lich, JD; Moore, CB; Iocca, HA; Roney, KE; Holl, EK; Wu, QP; van Deventer, HW; Fabry, Z; Ting, JP-Y
MLA Citation
O’Connor, Brian P., et al. “Semaphorin 6D regulates the late phase of CD4+ T cell primary immune responses..” Proc Natl Acad Sci U S A, vol. 105, no. 35, Sept. 2008, pp. 13015–20. Pubmed, doi:10.1073/pnas.0803386105.
URI
https://scholars.duke.edu/individual/pub1125450
PMID
18728195
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
105
Published Date
Start Page
13015
End Page
13020
DOI
10.1073/pnas.0803386105