Role of signaling pathways downstream of Pattern Recognition Receptors in the regulation of innate immunity
Innate immunity is the oldest form of immunity, already present in plants and invertebrates, and is based on evolutionarily ancient molecular mechanisms. Fundamental receptors of innate immunity are the Pattern Recognition Receptor (PRR) that recognize molecular structures belonging to microorganisms (PAMPs). PRR recognition of PAMPs determin the activation of molecular pathways, such as the NFkB pathway, preserved during evolution and the consequent response of the immune system. However, increasing evidence suggests that factors that appeared late in evolution, such as NFAT transcription factors, also regulate the functions of innate immune cells. The NFAT pathway has been well characterized in adaptive immunity, while there is little information on its role in innate immune cells. Recent studies indicate that this pathway is activated in innate immune cells of myeloid origin downstream of PRRs and suggests it has a fundamental role in controlling the cross-talk of myeloid cells with the endothelium and with innate and adaptive lymphocytes. These studies also suggest that the deregulation of the NFAT pathway in myeloid cells leads to the development of chronic inflammatory diseases.
Our research group studies the consequences of NFAT activation in innate immune cells in cases of microbial infection (fungi) and sterile inflammation (acute rejection), using appropriate mouse models and nanostructured NFAT inhibitors. The research group is also involved in studying the tumor-intrinsic and tumor-extrinsic role of NFAT in tumor growth and in the control of the tumor microenvironment.
- Study of the role of PRRs and the NFAT pathway in the activation and development of the inflammatory process in response to microbial stimuli.
- Study of the role of the NFAT signaling pathway in sterile inflammation.
- Study of the tumor-intrinsic and tumor-extrinsic role of NFAT in the control of tumor progression and the formation of the tumor microenvironment.
- Marongiu L, Gornati L, Artuso I, Zanoni I, Granucci F Below the surface: The inner lives of TLR4 and TLR9. J Leukoc Biol. 2019 Mar 22. doi: 10.1002/JLB.3MIR1218-483RR.
- Gornati L, Zanoni I, Granucci F. Dendritic Cells in the Cross Hair for the Generation of Tailored Vaccines. Front Immunol. 2018 Jun 27;9:1484. doi: 10.3389/fimmu.2018.01484. eCollection 2018.
- Granucci F. The Family of LPS Signal Transducers Increases: the Arrival of Chanzymes. Immunity. 2018 Jan 16;48(1):4-6. doi: 10.1016/j.immuni.2017.12.016.
- Santus W, Barresi S, Mingozzi F, Broggi A, Orlandi I, Stamerra G, Vai M, Martorana AM, Polissi A, Köhler JR, Liu N, Zanoni I, Granucci F. Skin infections are eliminated by cooperation of the fibrinolytic and innate immune systems. Sci Immunol. 2017 Sep 22;2(15). pii: eaan2725. doi: 10.1126/sciimmunol.aan2725.
- Prosperi D, Colombo M, Zanoni I, Granucci F. Drug nanocarriers to treat autoimmunity and chronic inflammatory diseases. Semin Immunol. 2017 Dec;34:61-67. doi: 10.1016/j.smim.2017.08.010. Epub 2017 Aug 30.
- Broggi A, Tan Y, Granucci F, Zanoni I. IFN-λ suppresses intestinal inflammation by non-translational regulation of neutrophil function. Nat Immunol. 2017 Oct;18(10):1084-1093. doi: 10.1038/ni.3821.
- Rusconi M, Gerardi F, Santus W, Lizio A, Sansone VA, Lunetta C, Zanoni I, Granucci F.
Inflammatory role of dendritic cells in Amyotrophic Lateral Sclerosis revealed by an analysis of patients’ peripheral blood. Sci Rep. 2017 Aug 10;7(1):7853. doi: 10.1038/s41598-017-08233-1.
- Mingozzi F, Spreafico R, Gorletta T, Cigni C, Di Gioia M, Caccia M, Sironi L, Collini M, Soncini M, Rusconi M, von Andrian UH, Chirico G, Zanoni I, Granucci F. Prolonged contact with dendritic cells turns lymph node-resident NK cells into anti-tumor effectors. EMBO Mol Med. 2016 Sep 1;8(9):1039-51. doi: 10.15252/emmm.201506164. Print 2016 Sep.
- Guglielmetti S, Zanoni I, Balzaretti S, Miriani M, Taverniti V, De Noni I, Presti I, Stuknyte M, Scarafoni A, Arioli S, Iametti S, Bonomi F, Mora D, Karp M, Granucci F. Murein lytic enzyme TgaA of Bifidobacterium bifidum MIMBb75 modulates dendritic cell maturation through its cysteine- and histidine-dependent amidohydrolase/peptidase (CHAP) amidase domain. Appl Environ Microbiol. 2014 Sep;80(17):5170-7. doi: 10.1128/AEM.00761-14. Epub 2014 May 9.
- Zanoni I, Spreafico R, Bodio C, Di Gioia M, Cigni C, Broggi A, Gorletta T, Caccia M, Chirico G, Sironi L, Collini M, Colombo MP, Garbi N, Granucci F. IL-15 cis presentation is required for optimal NK cell activation in lipopolysaccharide-mediated inflammatory conditions. Cell Rep. 2013 Sep 26;4(6):1235-49. doi: 10.1016/j.celrep.2013.08.021. Epub 2013 Sep 19.
- Vitali C, Mingozzi F, Broggi A, Barresi S, Zolezzi F, Bayry J, Raimondi G, Zanoni I, Granucci F.
Migratory, and not lymphoid-resident, dendritic cells maintain peripheral self-tolerance and prevent autoimmunity via induction of iTreg cells. Blood. 2012 Aug 9;120(6):1237-45. doi: 10.1182/blood-2011-09-379776. Epub 2012 Jul 3.
- Zanoni I, Ostuni R, Barresi S, Di Gioia M, Broggi A, Costa B, Marzi R, Granucci F. CD14 and NFAT mediate lipopolysaccharide-induced skin edema formation in mice. J Clin Invest. 2012 May;122(5):1747-57. doi: 10.1172/JCI60688. Epub 2012 Apr 2.
- Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC. CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell. 2011 Nov 11;147(4):868-80. doi: 10.1016/j.cell.2011.09.051.
- 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. CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation. Nature. 2009 Jul 9;460(7252):264-8. doi: 10.1038/nature08118. Epub 2009 Jun 14.