Dr. Fabio Re

Fabio Re, Ph.D.

Associate Professor

Office: 2.343, Telephone: (847) 578-8650

Lab: 2.406A-F, Telephone: (847) 578-7706

E-mail: fabio.re@rosalindfranklin.edu

Research Interests

The long-term goal of the research in my lab is to augment our understanding of the cellular and molecular mechanisms that govern innate and adaptive immunity. This is a prerequisite for the rational design of more successful immunotherapies and vaccination strategies. Innate immunity relies on the ability of cells of the immune system to recognize microbial products through pattern recognition receptors (PRR) such as the Toll-like receptors (TLR) and the

Nod-like receptors (NLR).

TLR are expressed on the cell surface or in endosomal compartments while NLR are expressed in the cytoplasm. Both families of receptors recognize microbial products and “danger signals” released by dead cells and activate signaling pathways that initiate the inflammatory response and regulate development of adaptive immunity. Stimulation through TLR results in activation of the NF-kB, MAPK, and IRF signaling pathways culminating in transcriptional induction of a large number of genes that encode for cytokines, chemokines, adhesion molecules and other proinflammatory mediators and leads to a profound reprogramming of the functions of antigen presenting cells.

NLR, in contrast, primarily lead to activation of the inflammasome, a multiprotein complex that contains, in addition to NLR, the adaptor molecule ASC and the protease caspase-1. Activation of caspase-1 in the context of the inflammasome is responsible for the proteolytic processing of the immature form of the cytokines belonging to the IL-1 family (IL-1b, IL-18, and IL-33), a modification required for their secretion. Synthesis of the immature form of these cytokines is induced by TLR agonists and proinflammatry cytokines (signal 1). Interleukin-1 family cytokines possess potent inflammatory activities and their unregulated production is the cause of several human inflammatory diseases.

My lab investigates the activation of TLR and NLR in two distinct experimental settings: Vaccine adjuvants and infection with the intracellular bacterium Francisella tularensis.

Vaccine Adjuvants

Adjuvants are substances that enhance the immunogenicity of a co-administered antigen in vivo and as such are an essential component of vaccines.Adjuvants are thought to mimic biological activities associated with live pathogens. For several decades aluminum hydroxide and aluminum phosphate, commonly known as alum, have been widely used as adjuvants for humans vaccination despite the fact that their mechanism of action remained elusive. Alum is unable to act as a TLR agonist and does not promote in vitro DC maturation, hence whether it is capable of directly triggering PRR was, until recently, unknown.

In a groundbreaking work, we have found that alum is capable of activating caspase-1 and inducing release of IL-1b and IL-18. This response is mediated by the NLR molecule NLRP3 and is triggered by other adjuvants, suggesting that inflamasome activation may be a common mechanism of action of adjuvants. Importantly, we have shown that the response of NLRP3-deficient mice to vaccines that contain alum is significantly impaired, thus demonstrating a role for the NLRP3-inflammasome during development of the adaptive immune response.

Our long-term goal is to understand the mechanism through which alum and other adjuvants activate the NLRP3 inflammasome and to determine the role of the IL-1 cytokines superfamily during vaccination and development of adaptive immunity. We are also interested in finding small molecules that activate the inflammasome and could be used as adjuvant. Finally, we are investigating activation of the inflammasome in cells undergoing necrosis.

Francisella tularensis

Francisella tularensis (Ft) is a Gram-negative facultative intracellular bacterium that causes tularemia. Although tularemia is a rare disease two main considerations drive the interest in Ft research. First, Ft is a potential bioterrorism agent. Secondly, Ft is an excellent model organism to study the interaction of intracellular bacteria with the host. Knowledge acquired studying Ft will increase our understanding of the biology of other intracellular bacteria that cause important human diseases.

Ft infects several cell types, most prominently macrophages, and rapidly escapes the phagosome and replicates within the cytoplasm of host cells. Very little is known at the molecular level about how Ft causes disease.

We and other groups have reported that the inflammatory response induced by Ft is primarily mediated by activation of TLR2 and the inflammasome. In the search for Ft factors capable of activating TLR2 we have identified two bacterial lipoproteins, TUL4 and FT1103, and determined that these proteins are capable of activating the TLR2/TLR1 heterodimer, suggesting they are triacylated lipoproteins. We have also characterized at the molecular level their interaction with the extracellular domain of TLR2. The mechanism responsible for activation of the inflammasome by Ft remains a mystery. The main goal of our research in this area is to identify the Ft-derived factors or mechanisms responsible for triggering the inflammasome and the NLR molecules that mediate inflammasome activation by Ft. We are also interested in determining the role of the inflammasome in the pathogenesis of tularemia.

Role of the inflammasome in Cancer

The link between cancer and inflammation is well documented. Inflammation promotes malignant transformation and, conversely, tumorigenesis triggers an inflammatory response. Cancer-related inflammation favors tumor development and progression by affecting the mutagenesis rate, by enhancing tumor cells’ survival and growth, by establishing an immune-suppressive tumor microenvironment, and by promoting angiogenesis and metastatic dissemination of the primary tumor. Interleukin-1b is one of the proinflammatory cytokines that more strongly promotes cancer development. We have shown that the NLRP3-inflammasome is intrinsically activated in necrotic cells. Necrosis is often observed in the internal regions of tumors where nutrients and oxygen supply is limited. However, it is still unclear whether the inflammasome is activated in the tumor microenvironment and how this may affect tumor progression. Our studies will increase the understanding of how cancer-related inflammation is initiated and sustained and will support the notion that novel therapeutic approaches that target the inflammatory components of tumors will result in more effective treatments.

Recent Publications

2006

Li, H, Nookala, S., Bina, X. W., Bina, J. E., and Re, F. “Innate immune response to Francisella tularensis is mediated by TLR2 and caspase-1 activation.” J. Leuk. Biol. 80: 766-773, 2006.

Prohinar, P., Re, F., Widstrom, R., Zhang, D., Teghanemt, A., Weiss, J. P., and Gioannini, T. L. “Specific high affinity interactions of monomeric endotoxin: protein complexes with Toll-like receptor 4 ectodomain.” J. Biol. Chem. 282:1010-1017, 2006.

Cao, F., Castrillo, A., Tontonoz, P., Re, F., Byrne, G.I. “Chlamydia pneumoniae-induced Macrophage Foam Cell Formation Is Mediated by Toll-Like Receptor 2.” Infect Immun. 75:753-759, 2006.

Li, H., Nookala, S., and Re, F. “Alum Adjuvants Activate Caspase-1 And Induce IL-1 And IL-18 Release.” J. Immunol. 178:5271-5276, 2006.

2007

Teghanemt, A., Re, F., Prohinar, P., Widstrom, R., Gioannini, T. L., and Weiss, J. P. “Novel roles in human MD-2 of phenylalanine 121 and 126 and tyrosine 131 in activation of Toll-like Receptor 4 by endotoxin.” J. Biol. Chem. 283:1257-1266, 2007.

2008

Li, H., Nooh, M.M., Kotb, M., and Re, F. “Commercial peptidoglycan preparations are contaminated with superantigen-like activity that stimulates IL-17 production.” J. Leuk. Biol. 83:409-418, 2008.

Thakran, S., Li, H., Lavine, C.L., Miller, M. A., Bina, J. E., Bina, X. R., Re, F. “ Identification of Francisella tularensis lipoproteins that stimulate the Toll-like receptor (TLR) 2/TLR1 heterodimer.” J. Biol. Chem. 283:3751-3760, 2008.

Nance, S.C., Yi, A.K., Re, F., Fitzpatrick, E. A. “MyD88 is necessary for neutrophil recruitment in hypersensitivity pneumonitis.” J. Leukoc. Biol. 83:1207-1217, 2008.

Li, H., Willingham,S. B., Ting,J. P.-Y., and Re, F. “Cutting Edge: Inflammasome activation by Alum and Alum’s adjuvant effect are mediated by NLRP3.” J. Immunol. 181:17-21, 2008.

2009

Li, H., Ambade, A., and Re, F. “ Cutting Edge: Necrosis activates the NLRP3 inflammasome.” J. Immunol. 183:1528-1532, 2009.

2010

Re, F. “Inflammasome activation by pathogenic crystals and particles.” Prog. Inflamm. Res. (Martinon, F., Couillin, I., Petrilli, V., eds) (in press)

Tsukahara, T., Tsukahara, R., Fujiwara, Y., Yue, J., Cheng, Y., Guo, H., Bolen, A., Zhang, C., Balazs, L., Re, F., Du, G., Frohman, M. A., Baker, D. L., Parrill, A. L., Uchiyama, A., Kobayashi, T., Murakami-Murofushi, K., and Tigyi, G. “Phospholipase D2-dependent Inhibition of the Nuclear Hormone Receptor PPARγ by Cyclic Phosphatidic Acid.” Molec. Cell 39:421-432, 2010.

2011

Jayakar HR, Parvathareddy J, Fitzpatrick EA, Bina XR, Bina JE, Re F, Emery FD, Miller MA. “A galU mutant of francisella tularensis is attenuated for virulence in a murine pulmonary model of tularemia.” BMC Microbiol. Aug 5;11:179, 2011.

Ceballos-Olvera I, Sahoo M, Miller MA, Barrio Ld, Re F, "Inflammasome-dependent Pyroptosis and IL-18 Protect against Burkholderia pseudomallei Lung Infection while IL-1β Is Deleterious." PLoS Pathog 7(12): e1002452. doi:10.1371/journal.ppat.1002452, Dec 2011.

Updated: 01.12.12