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Wang, Donghai

Overview:

Inflammation underlies a variety of human diseases such as obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, arthritis and cancer. Together, these diseases constitute a major challenge to the well being of modern human society. Understanding the fundamental mechanisms of inflammation may provide rationales for designing novel interventions to treat these maladies. Autoinflammatory diseases are an emerging family of illness, characterized by dysregulation of innate immune responses. Studies of these hereditary human disorders have provided invaluable insight into basic cellular and molecular mechanisms of the innate immune responses and have contributed significantly to the development of targeted therapies for common human inflammatory diseases such as arthritis. My long term goal is to understand the pathophysiological mechanisms of autoinflammatory diseases and to apply knowledge from such studies to develop novel treatment of inflammatory human diseases. Our recent studies of one of such diseases, namely mevalonate kinase deficiency, has allowed us to unravel the unexpected connection between the cholesterol-biosynthesis mevalonate pathway and toll like receptor (TLR)-mediated phosphatidyl inosital 3(PI3)-kinase signaling. These exciting new discoveries will greatly advance our knowledge of innate immune signaling and may provide clues for new interventions of a variety of human diseases.

Positions:

Assistant Professor in Medicine

Medicine, Rheumatology and Immunology
School of Medicine

Assistant Professor in Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2004

Ph.D. — Sun Yat Sen University (China)

Grants:

Organization and Function of Cellular Structure

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1975
End Date
June 30, 2020

Censoring Inflammation by Protein Geranylgeranylation

Administered By
Medicine, Rheumatology and Immunology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
December 01, 2014
End Date
November 30, 2019

Basic Immunology Training Program

Administered By
Immunology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2002
End Date
June 30, 2019

Innate Immune Inhibition of the Mevalonate Pathway Impairs Neurodevelopment during ZIKV Infection

Administered By
Medicine, Rheumatology and Immunology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 2017
End Date
April 30, 2019

Regulation of Inflammation by the Mevalonate Pathway in Mouse Model of RA

Administered By
Medicine, Rheumatology and Immunology
AwardedBy
Arthritis Foundation
Role
Principal Investigator
Start Date
November 01, 2015
End Date
April 30, 2016
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Publications:

IL-27 Facilitates Skin Wound Healing through Induction of Epidermal Proliferation and Host Defense.

Skin wound repair requires a coordinated program of epithelial cell proliferation and differentiation as well as resistance to invading microbes. However, the factors that trigger epithelial cell proliferation in this inflammatory process are incompletely understood. In this study, we demonstrate that IL-27 is rapidly and transiently produced by CD301b+ cells in the skin after injury. The functional role of IL-27 and CD301b+ cells is demonstrated by the finding that CD301b-depleted mice exhibit delayed wound closure in vivo, which could be rescued by topical IL-27 treatment. Furthermore, genetic ablation of the IL-27 receptor (Il27Ra-/-) attenuates wound healing, suggesting an essential role for IL-27 signaling in skin regeneration in vivo. Mechanistically, IL-27 feeds back on keratinocytes to stimulate cell proliferation and re-epithelialization in the skin, whereas IL-27 leads to suppression of keratinocyte terminal differentiation. Finally, we identify that IL-27 potently increases expression of the antiviral oligoadenylate synthetase 2, but does not affect expression of antibacterial human beta defensin 2 or regenerating islet-derived protein 3-alpha. Together, our data suggest a previously unrecognized role for IL-27 in regulating epithelial cell proliferation and antiviral host defense during the normal wound healing response.

Authors
Yang, B; Suwanpradid, J; Sanchez-Lagunes, R; Choi, HW; Hoang, P; Wang, D; Abraham, SN; MacLeod, AS
MLA Citation
Yang, B, Suwanpradid, J, Sanchez-Lagunes, R, Choi, HW, Hoang, P, Wang, D, Abraham, SN, and MacLeod, AS. "IL-27 Facilitates Skin Wound Healing through Induction of Epidermal Proliferation and Host Defense." May 2017.
PMID
28132857
Source
epmc
Published In
Journal of Investigative Dermatology
Volume
137
Issue
5
Publish Date
2017
Start Page
1166
End Page
1175
DOI
10.1016/j.jid.2017.01.010

The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation.

Type III secretion systems (T3SS) are central virulence factors for many pathogenic Gram-negative bacteria, and secreted T3SS effectors can block key aspects of host cell signaling. To counter this, innate immune responses can also sense some T3SS components to initiate anti-bacterial mechanisms. The Yersinia pestis T3SS is particularly effective and sophisticated in manipulating the production of pro-inflammatory cytokines IL-1β and IL-18, which are typically processed into their mature forms by active caspase-1 following inflammasome formation. Some effectors, like Y. pestis YopM, may block inflammasome activation. Here we show that YopM prevents Y. pestis induced activation of the Pyrin inflammasome induced by the RhoA-inhibiting effector YopE, which is a GTPase activating protein. YopM blocks YopE-induced Pyrin-mediated caspase-1 dependent IL-1β/IL-18 production and cell death. We also detected YopM in a complex with Pyrin and kinases RSK1 and PKN1, putative negative regulators of Pyrin. In contrast to wild-type mice, Pyrin deficient mice were also highly susceptible to an attenuated Y. pestis strain lacking YopM, emphasizing the importance of inhibition of Pyrin in vivo. A complex interplay between the Y. pestis T3SS and IL-1β/IL-18 production is evident, involving at least four inflammasome pathways. The secreted effector YopJ triggers caspase-8- dependent IL-1β activation, even when YopM is present. Additionally, the presence of the T3SS needle/translocon activates NLRP3 and NLRC4-dependent IL-1β generation, which is blocked by YopK, but not by YopM. Taken together, the data suggest YopM specificity for obstructing the Pyrin pathway, as the effector does not appear to block Y. pestis-induced NLRP3, NLRC4 or caspase-8 dependent caspase-1 processing. Thus, we identify Y. pestis YopM as a microbial inhibitor of the Pyrin inflammasome. The fact that so many of the Y. pestis T3SS components are participating in regulation of IL-1β/IL-18 release suggests that these effects are essential for maximal control of innate immunity during plague.

Authors
Ratner, D; Orning, MPA; Proulx, MK; Wang, D; Gavrilin, MA; Wewers, MD; Alnemri, ES; Johnson, PF; Lee, B; Mecsas, J; Kayagaki, N; Goguen, JD; Lien, E
MLA Citation
Ratner, D, Orning, MPA, Proulx, MK, Wang, D, Gavrilin, MA, Wewers, MD, Alnemri, ES, Johnson, PF, Lee, B, Mecsas, J, Kayagaki, N, Goguen, JD, and Lien, E. "The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation." PLoS pathogens 12.12 (December 2, 2016): e1006035-.
PMID
27911947
Source
epmc
Published In
PLoS pathogens
Volume
12
Issue
12
Publish Date
2016
Start Page
e1006035
DOI
10.1371/journal.ppat.1006035

Control of the innate immune response by the mevalonate pathway.

Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages that were deficient in GGTase I or p110δ exhibited constitutive release of interleukin 1β that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.

Authors
Akula, MK; Shi, M; Jiang, Z; Foster, CE; Miao, D; Li, AS; Zhang, X; Gavin, RM; Forde, SD; Germain, G; Carpenter, S; Rosadini, CV; Gritsman, K; Chae, JJ; Hampton, R; Silverman, N; Gravallese, EM; Kagan, JC; Fitzgerald, KA; Kastner, DL; Golenbock, DT; Bergo, MO; Wang, D
MLA Citation
Akula, MK, Shi, M, Jiang, Z, Foster, CE, Miao, D, Li, AS, Zhang, X, Gavin, RM, Forde, SD, Germain, G, Carpenter, S, Rosadini, CV, Gritsman, K, Chae, JJ, Hampton, R, Silverman, N, Gravallese, EM, Kagan, JC, Fitzgerald, KA, Kastner, DL, Golenbock, DT, Bergo, MO, and Wang, D. "Control of the innate immune response by the mevalonate pathway." Nature immunology 17.8 (August 2016): 922-929.
Website
http://hdl.handle.net/10161/12409
PMID
27270400
Source
epmc
Published In
Nature Immunology
Volume
17
Issue
8
Publish Date
2016
Start Page
922
End Page
929
DOI
10.1038/ni.3487

Inflammation in Mice Ectopically Expressing Human Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne (PAPA) Syndrome-associated PSTPIP1 A230T Mutant Proteins

Authors
Wang, D; Höing, S; Patterson, HC; Ahmad, UM; Rathinam, VAK; Rajewsky, K; Fitzgerald, KA; Golenbock, DT
MLA Citation
Wang, D, Höing, S, Patterson, HC, Ahmad, UM, Rathinam, VAK, Rajewsky, K, Fitzgerald, KA, and Golenbock, DT. "Inflammation in Mice Ectopically Expressing Human Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne (PAPA) Syndrome-associated PSTPIP1 A230T Mutant Proteins." Journal of Biological Chemistry 288.7 (February 15, 2013): 4594-4601.
Website
http://hdl.handle.net/10161/11514
Source
crossref
Published In
The Journal of biological chemistry
Volume
288
Issue
7
Publish Date
2013
Start Page
4594
End Page
4601
DOI
10.1074/jbc.M112.443077

The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens

Authors
Hsu, Y-MS; Zhang, Y; You, Y; Wang, D; Li, H; Duramad, O; Qin, X-F; Dong, C; Lin, X
MLA Citation
Hsu, Y-MS, Zhang, Y, You, Y, Wang, D, Li, H, Duramad, O, Qin, X-F, Dong, C, and Lin, X. "The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens." Nature Immunology 8.2 (February 2007): 198-205.
Website
http://hdl.handle.net/10161/11515
Source
crossref
Published In
Nature Immunology
Volume
8
Issue
2
Publish Date
2007
Start Page
198
End Page
205
DOI
10.1038/ni1426

3-Hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin)-induced 28-kDa interleukin-1ß interferes with mature IL-1ß signaling

Authors
Wang, D
MLA Citation
Wang, D. "3-Hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin)-induced 28-kDa interleukin-1ß interferes with mature IL-1ß signaling." The Journal of biological chemistry.
Website
http://hdl.handle.net/10161/11513
Source
manual
Published In
The Journal of biological chemistry

Bcl10 plays a critical role in NF-kappaB activation induced by G protein-coupled receptors

Authors
Wang, D; Lin,
MLA Citation
Wang, D, and Lin, . "Bcl10 plays a critical role in NF-kappaB activation induced by G protein-coupled receptors."
Website
http://hdl.handle.net/10161/11516
Source
manual

Phosphorylation of CARMA1 plays a critical role in T Cell receptor-mediated NF-kappaB activation

Authors
Wang, D
MLA Citation
Wang, D. "Phosphorylation of CARMA1 plays a critical role in T Cell receptor-mediated NF-kappaB activation."
Website
http://hdl.handle.net/10161/11517
Source
manual

CD3/CD28 costimulation-induced NF-kappaB activation is mediated by recruitment of protein kinase C-theta, Bcl10, and IkappaB kinase beta to the immunological synapse through CARMA1

A requirement for CARMA1 in TCR-induced NF-kappa B activation.

Authors
Wang, D
MLA Citation
Wang, D. "A requirement for CARMA1 in TCR-induced NF-kappa B activation."
Website
http://hdl.handle.net/10161/11519
Source
manual

Cytoplasmic Igα Serine/Threonines Fine-Tune Igα Tyrosine Phosphorylation and Limit Bone Marrow Plasma Cell Formation

Authors
Wang, D
MLA Citation
Wang, D. "Cytoplasmic Igα Serine/Threonines Fine-Tune Igα Tyrosine Phosphorylation and Limit Bone Marrow Plasma Cell Formation."
Website
http://hdl.handle.net/10161/11520
Source
manual

Sox4 Is Required for the Survival of Pro-B Cells

Authors
Wang, D
MLA Citation
Wang, D. "Sox4 Is Required for the Survival of Pro-B Cells."
Website
http://hdl.handle.net/10161/11521
Source
manual

Malaria-Induced NLRP12/NLRP3-Dependent Caspase-1 Activation Mediates Inflammation and Hypersensitivity to Bacterial Superinfection

Authors
Wang, D
MLA Citation
Wang, D. "Malaria-Induced NLRP12/NLRP3-Dependent Caspase-1 Activation Mediates Inflammation and Hypersensitivity to Bacterial Superinfection."
Website
http://hdl.handle.net/10161/11522
Source
manual

CARMA3 deficiency abrogates G protein-coupled receptor-induced Nf-kB activation

Authors
Wang, D
MLA Citation
Wang, D. "CARMA3 deficiency abrogates G protein-coupled receptor-induced Nf-kB activation."
Website
http://hdl.handle.net/10161/11523
Source
manual
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