> Skip repeated content
photo of Xiaoyu Hu, MD, PhD

Xiaoyu Hu, MD, PhD

About Dr. Hu


Regulation of Inflammation by Notch signaling

Notch signaling pathway is conserved from Drosophila to mammals and has well-established roles in cell fate decision and organism development. Interestingly, Notch pathway components and target genes are expressed under inflammatory conditions, including rheumatoid arthritis and atherosclerosis. However, the role of Notch pathway in regulation of inflammation remains unknown. Recently, we found that canonical Notch target genes are induced in macrophages by stimulation of toll like receptors (TLRs), a group of pattern recognition receptors that recognize pathogen-associated molecular patterns. Further investigation revealed that Notch and TLR pathways cooperated to activate canonical Notch target genes, including transcriptional repressors Hes1 and Hey1, and to increase production of canonical TLR-induced cytokines tumor necrosis factor (TNF), interleukin (IL)-6 and IL-12. Cooperation by these pathways to increase target gene expression was mediated by the Notch pathway component and transcription factor RBP-J, which also contributed to lethality after endotoxin injection. TLR- and Notch-induced Hes1 and Hey1 attenuated IL-6 and IL-12 production. These findings identify new immune functions for RBP-J, Hes and Hey proteins and provide insights into mechanisms by which Notch and TLR signals are integrated to modulate specific aspects of inflammation.

Although our original observations established a novel crosstalk between Notch and TLR pathways, there are many unanswered questions regarding the mechanisms of regulation and biological significance of such crosstalk. We are taking rigorous genetic approaches to address the role of Notch pathway in vivo and biochemical and molecular biology approaches to perform the mechanistic studies in vitro. We anticipate that our research will yield insights into selective regulation of inflammatory responses that can be exploited for therapeutic interventions to suppress inflammation in autoimmune diseases. Three major areas of investigation are currently ongoing:

  1. Elucidation of mechanisms by which TLR and Notch pathways synergize to activate macrophage gene expression
  2. Characterization of the role of Notch signaling in macrophage responses and inflammation in vitro and in vivo
  3. Investigation of the functions of TLR/Notch target genes Hes1 and Hey1 in immune/inflammatory responses and the mechanisms of action



Assistant Scientist, Arthritis and Tissue Degeneration Program, Hospital for Special Surgery
Assistant Professor of Immunology, Department of Medicine, Weill Cornell Medical College



Publications by Dr. Hu

Selected Publications

Hu X, Herrero C, Li WP, Antoniv TT, Falck-Pedersen E, Koch AE, Woods JM, Haines GK III, Ivashkiv LB. Sensitization of Interferon-gamma Jak-STAT signaling during macrophage activation. Nature Immunology 2002; 3:859-866.

Hu X, Li WP, Meng C, Ivashkiv LB. Inhibition of Interferon-gamma signaling by glucocorticoids. Journal of Immunology 2003; 170:4833-4839.

Tassiulas I, Hu X, Ho HH, Kashyap Y, Paik PK, Hu Y, Lowell CA, Ivashkiv LB. Amplification of IFN-alpha-induced STAT1 activation and inflammatory function by Syk and ITAM-containing adaptors. Nature Immunology 2004; 5:1181-1189.

Hu X, Ho HH, Lou O, Hidaka C, Ivashkiv LB. Homeostatic role of Interferons conferred by inhibition of IL-1-mediated inflammation and tissue destruction. Journal of Immunology 2005; 175:131-138.

Hu X, Park-Min K, Ho HH, Ivashkiv LB. IFN-gamma-primed macrophages exhibit increased CCR2-dependent migration and altered IFN-gamma responses mediated by Stat1. Journal of Immunology 2005; 175:3637-3647.

Hu X, Paik PK, Chen J, Yarilina A, Kockeritz L, Lu TT, Woodgett JR, Ivashkiv LB. IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating glycogen synthase kinase-3 and CREB/AP-1 proteins. Immunity 2006; 24:563-574.

Hu X, Chen J, Wang L, Ivashkiv LB. Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation. Journal of Leukocyte Biology 2007; 82:237-243.

Yarilina A, Park-Min KH, Antoniv TT, Hu X, Ivashkiv LB. TNF activates an IRF1-dependent autocrine loop leading to sustained expression of chemokines and STAT1-dependent IFN response genes. Nature Immunology 2008; 9:378-387.

Hu X, Chung AY, Wu I, Foldi J, Chen J, Ji J, Tateya T, Gessler M, Kageyama R, Ivashkiv LB. Selective and reciprocal regulation of TLR-inducible gene subsets by Notch and IFN-gamma pathways. Immunity 2008; 29:691-703.

Hu X, Chakravarty SD, Ivashkiv LB. Regulation of inflammatory signaling by opposing feed-forward and feedback inhibition mechanisms. Immunological Reviews 2008; 226:41-56.

Zhao B, Takami M, Yamada A, Wang X, Koga T, Hu X, Tamura T, Ozato K, Choi Y, Ivashkiv LB, Takayanagi H, Kamijo R. Interferon regulatory factor 8 regulates bone metabolism by suppressing osteoclastogenesis. Nature Medicine 2009; 15:1066-1071 

Hu X, Ivashkiv LB. Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases. Immunity 2009; 31:539-550 

Foldi J, Chung AY, Xu H, Zhu J, Outtz HH, Kitajewski J, Li Y, Hu X*, Ivashkiv LB*. Autoamplification of Notch signaling in macrophages by TLR-induced and RBP-J-dependent induction of Jagged1. Journal of Immunology 2010; 185:5023-5031 (*co-corresponding author) 

Alvarez Y, Municio C, Hugo E, Zhu J, Alonso S, Hu X, Fernández N, Sánchez Crespo M. Notch and TLE-dependent histone deacetylation explains IL-12p70 inhibition by zymosan. Journal of Biological Chemistry 2011; 286:16583-16595 

Park SH, Park-Min KH, Chen J, Hu X, Ivashkiv LB. TNF induces cross-tolerance to endotoxin that is mediated by GSK3 in macrophages. Nature Immunology 2011; 12:607-615 

Dai P, Cao H, Merghoub T, Francesca A, Wang W, Parikh T, Fang C-M, Pitha PM, Fitzgerald KA, Rahman MM, McFadden G, Hu X, Houghton AN, Shuman S, Deng L. Myxoma virus induces type I IFN production in murine plasmacytoid dendritic cells via a TLR9/MyD88, IRF5/IRF7, and the type I IFN receptor-dependent pathway. Journal of Biological Chemistry 2011; 85:10814-10825 

Zhao B, Grimes S, Li S, Hu X, Ivashkiv LB. TNF-induced osteoclastogenesis and inflammatory bone resorption regulated by transcription factor RBP-J. Journal of Experimental Medicine 2012; 209:319-334 

Xu H, Zhu J, Smith S, Foldi J, Zhao B, Chung AY, Outtz HH, Kitajewski J, Shi C, Weber S, Saftig P, Li YM, Ozato K, Blobel CP, Ivashkiv LB, and Hu X. Notch-RBP-J signaling regulates IRF8 to promote inflammatory macrophage polarization. Nature Immunology 2012; 13:642-650


For more publications, please see the PubMed listing.

Industry Relationships

Industry Relationships

One of the goals of HSS is to advance the science of orthopedic surgery, rheumatology, and related disciplines for the benefit of patients. Research staff at HSS may collaborate with outside companies for education, research and medical advances. HSS supports this collaboration in order to foster medical breakthroughs; however, HSS also believes that these collaborations must be disclosed.

As part of the disclosure process, this website lists Research staff collaborations with outside companies if the Research staff member received any payment during the prior year or expects to receive any payment in the next year. The disclosures are based on information provided by the Research staff and other sources and are updated regularly. Current ownership interests and leadership positions are also listed. Further information may be available on individual company websites.

As of April 22, 2015, Dr. Hu reported no relationships with healthcare industry.

By disclosing the collaborations of HSS Research staff with industry on this website, HSS and its Research staff make this information available to patients and the public, thus creating a transparent environment for those who are interested in this information. Further, the HSS Conflicts of Interest Policy does not permit payment of royalties on products developed by him/her that are used on patients at HSS.

Dr. Hu in the News