Macrophages are key innate immune cells playing fundamental roles during tissue homeostasis and microbial infections. Accordingly, alterations of their functional properties underlie a wide range of human pathologies including autoimmunity, neurodegenerative diseases, and cancer. Our Group uses a multidisciplinary approach integrating immunologic, genomic and genome editing tools to dissect the genetic and epigenetic principles of macrophage functions in vivo. We are particularly interested in understanding the contribution of non-coding regulatory elements, namely transcriptional enhancers, to the insurgence of inflammatory diseases. To this aim, we employ clinically relevant models of microbial infections and inflammatory pathologies such as Alzheimer’s disease and cancer to study the regulation of transcriptional enhancers in macrophages in these settings. Our long-term goal is to identify novel and specific intervention strategies to modulate macrophage functions for diagnostic and therapeutic purposes.

Curriculum Vitae

Research Positions

2015 – present: GROUP LEADER at Telethon Institute for Gene Therapy (TIGET)-San Raffaele, Milan (IT)

2011 – 2015: POST-DOCTORAL associate at European Institute of Oncology (IEO), Milan (IT)

Supervisor: Gioacchino Natoli, MD

2012: VISITING SCIENTIST at the Weizmann Institute of Science, Dept. of Immunology (Rehovot, Israel).

Supervisor: Prof. Ido Amit, PhD

2010: PhD in Translational and Molecular Medicine (DIMET) at University of Milano-Bicocca, Milan (IT)

Supervisors: Prof. Francesca Granucci, PhD and Dr. Ivan Zanoni, PhD; Prof. Luke O’Neill, PhD (Trinity College Dublin).

 

Education and Training

2007: Master’s degree in Industrial Biotechnology at University of Milano-Bicocca (110/110 cum laude)

2005: Bachelor’s degree in Biotechnology at University of Milano–Bicocca (110/110 cum laude)

 

Honors and Awards

– 2013: “Bioeconomy Rome Award” for outstanding achievements of young Italian investigators.

– 2012: “EMBO Short-Term Fellowship” to support research training at Weizmann Institute of Science (Israel).

– 2010: “Structured International Post Doc (SIPOD)” Fellowship at European Institute of Oncology (IEO).

– 2008: National PhD Fellowship from Italian Ministry of University and Research at University of Milano-Bicocca.

 

Invited Talks and Seminars

2015:

– 8th TRR81 PhD Minisymposium on “HDACs, HATs & gene regulation”, Institute of Molecular Biology and Tumor Research (IMT), Marburg (Germany).

– 49th Annual Meeting of the European Society for Clinical Investigation (ESCI), Cluj-Napoca (Romania)

– CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna (Austria). Host: Giulio Superti-Furga

– Humanitas Clinical and Research Center, Milan (Italy). Host: Antonio Sica

– Telethon Institute for Gene Therapy (TIGET). Host: Luigi Naldini

2013:

– “MiChroNetwork Meeting”, Milan (Italy)

– IFOM-IEO Campus, Milan (Italy)

2012:

– University of Milano-Bicocca (Italy). Host: Ivan Zanoni

– European Macrophage and Dendritic cell Society Meeting , Debrecen (Hungary)

– Weizmann Institute of Science (Israel). Host: Ido Amit

– 2nd MMI Meeting, Milan (Italy)

– IFOM-IEO Campus, Milan (Italy)

2010:

– University of California in San Diego (USA). Host: Michael Karin

– London Research Institute (UK). Host: Caetano Reis e Sousa

– University of Lausanne (Switzerland). Host: Jurg Tschopp

2008:

– “International Workshop on Gene Signalling Pathway Analysis and Representation for the Dendritic Cells”, Florence (Italy)

– “3rd DC-THERA Graduate School”, Celerina-Sankt Moritz (Switzerland)

– “In vivo non linear microscopy course” at Institute Curie, Paris (France)

 

Teaching Activities

– Seminars for “Genomics” course, PhD program in Molecular Oncology (SEMM), European Institute of Oncology (IEO)

– Lecturer for “Laboratory course in Immunology”, degree in Biotechnology, University of Milano–Bicocca

– Classes for “Immunology” and “Molecular Immunology” courses, degree in Biotechnology, University of Milano–Bicocca

– Mentor for >5 undergraduate and PhD student

Research Activity

Macrophages are plastic cells, meaning that they can adapt to environmental changes via highly coordinated rearrangements of their gene expression programs. For instance, macrophages exposed to pro- or anti-inflammatory signals such as lipopolysaccharide (LPS), interferon-gamma (IFNg)  or interleukin-4 (IL-4) acquire diverse transcriptional features (Murray et al., Immunity 2014). This occurrence also underlies the activities of macrophages in vivo, as tissue-resident macrophages are exposed to specific environmental signals driving the acquisition of tissue-selective functional properties (e.g. liver vs brain macrophages). Understanding the genomic effects of these stimuli is therefore essential to dissect the complex activities of macrophages during diseases, such as cancers, which are characterized by an aberrant development of microenvironmental niches (Ostuni et al., Trends in Immunology 2015).

Using state-of-the-art genomic technologies, we described the dynamic behavior of cis-regulatory elements in macrophages exposed to environmental signals, and dissected how stimulus-dependent activation of transcriptional enhancers controls macrophage activation.

This work led to the identification of latent enhancers, a novel class of regulatory elements that are formed de novo in terminally differentiated cells upon external stimulation (Ostuni et al., Cell 2013). Importantly, latent enhancers persist after termination of the inducing signal to mediate longer-term transcriptional and epigenetic memory, a process likely underlying the recently described features of “trained immunity” (Saeed et al., Science 2014). These findings describe a fundamental mechanism controlling macrophage plasticity in response to external stimulations. Moreover, they suggest that acquisition of persistent genomic rearrangements upon transient exposure to environmental signals may impact on subsequent macrophage  responses to physio/pathological stimuli. Our research activity will address this hypothesis in clinically relevant settings characterized by persistent environmental alterations such as microbial infections, human myelopoiesis or acquisition of secondary drug resistance by cancer cells.

Another area of active research in the laboratory is centered on the hypothesis that genetic or epigenetic alterations affecting the activity of macrophage enhancers may underlie the pathologic functions of these cells during inflammatory diseases. Our research will integrate transcriptional and chromatin profiling, computational analyses and advanced genome editing technologies to mechanistically dissect the biological functions of inflammatory gene enhancers in macrophages. These data will generate a framework to functionally interpret the effects of genetic variation in the noncoding genome on innate immune responses, possibly translating into clinically relevant outcomes.

Publications

1. Ostuni R, Kratochvill F, Murray PJ, Natoli G. Macrophages and cancer: from mechanisms to therapeutic implications.
Trends in Immunology. 2015 Apr;36(4):229-39. Co-corresponding author

2. Mancino A, Termanini A, Barozzi I, Ghisletti S, Ostuni R, Prosperini E, Ozato K, Natoli G. A dual cis-regulatory code links IRF8 to constitutive and inducible gene expression in macrophages.
Genes and Development. 2015 Feb 15;29(4):394-408.

3. Zimmermann M, Aguilera FB, Castellucci M, Rossato M, Costa S, Lunardi C, Ostuni R, Girolomoni G, Natoli G, Bazzoni F, Tamassia N, Cassatella MA. Chromatin remodeling and autocrine TNF-alpha are required for optimal interleukin-6 expression in activated human neutrophils. Nature Communications. 2015 Jan 23;6:6061.

4. Ostuni R, Natoli G. Lineages, cell types and functional states: a genomic view.
Current Opinion in Cell Biology. 2013 Dec;25(6):759-64. Co-corresponding author

5. Tamassia N, Zimmermann M, Castellucci M, Ostuni R, Bruderek K, Schilling B, Brandau S, Bazzoni F, Natoli G, Cassatella MA. Cutting Edge: An Inactive Chromatin Configuration at the IL-10 Locus in Human Neutrophils. Journal of Immunology. 2013 Mar 1;190(5):1921-5.

6. Ostuni R, Piccolo V, Barozzi I, Polletti S, Termanini A, Bonifacio S, Curina A, Prosperini E, Ghisletti S, Natoli G. Latent enhancers activated by stimulation in differentiated cells. Cell. 2013 Jan 17;152(1-2):157-71. Co-corresponding author

7. Austenaa L, Barozzi I, Chronowska A, Termanini A, Ostuni R, Prosperini E, Stewart AF, Testa G, Natoli G (2012). The Histone Methyltransferase Wbp7 Controls Macrophage Function through GPI Glycolipid Anchor Synthesis. Immunity. 2012 Apr 20;36(4):572-85.

8. Zanoni I, Ostuni R, Barresi S, Di Gioia M, Broggi A, Costa B, Marzi R, Granucci F (2012). CD14 and NFAT mediate lipopolysaccharide-induced skin edema formation in mice. Journal of Clinical Investigations. 2012 May 1;122(5):1747-57. Co-first author

9. Zanoni I, Bodio C, Broggi A, Ostuni R, Caccia M, Collini M, Venkatesh A, Spreafico R, Capuano G, Granucci F (2012). Similarities and differences of innate immune responses elicited by smooth and rough LPS. Immunology Letters. 2012 Feb 29;142(1-2):41-7.

10. Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC (2011). CD14 Controls the LPS-Induced Endocytosis of Toll-like Receptor 4. Cell. 2011 Nov 11;147(4):868-80.

11. Ostuni R, Natoli G (2011). Transcriptional control of macrophage diversity and specialization. European Journal of Immunology. 2011 Sep;41(9):2486-90.

12. Cavalieri D et al. (2010). DC-ATLAS: a systems biology resource to dissect receptor specific signal transduction in dendritic cells. Immunome Research. 2010 Nov 19;6:10.

13. Ostuni R, Zanoni I, Granucci F (2010). Deciphering the complexity of Toll-like receptor signaling. Cellular and Molecular Life Sciences. 2010 Dec;67(24):4109-34.

14. Zanoni I, Ostuni R, Capuano G, Collini M, Caccia M, Ronchi AE, Rocchetti M, Mingozzi F, Foti M, Chirico G, Costa B, Zaza A, Ricciardi-Castagnoli P, Granucci F (2009). CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation.
Nature. 2009 Jul 9;460(7252):264-8.