Intercellular communication in inflammatory response
P-selectin glycoprotein ligand-1 (PSGL-1) is a leukocyte receptor that interacts with selectins P, E and L and is responsible for the initial stages of extravasation of leukocytes to sites of inflammation. The group has described how PSGL-1 acts as an immunoregulatory receptor involved in the generation of regulatory T-cells (Treg) and contributes to the maintenance of peripheral tolerance in mice. Thus, mice deficient in PSGL-1 (PSGL-1 KO) develop a progressive autoimmune disease similar to systemic sclerosis (SSc).
Additionally, it has been observed that mice deficient in P-selectin develop an autoimmune syndrome that, unlike in PSGL-1 KO mice, generates anti-dsDNA antibodies, does not show fibrosis in the skin but develops inflammation in the hypodermis with lipoatrophy, shows lung and kidney involvement, and with ageing develops immune complex deposits in the skin and kidneys, characteristics similar to systemic lupus erythematosus (SLE). Notably, aged KO mice, both P-selectin and PSGL1, have thickened pulmonary capillaries, suggesting that they may develop pulmonary hypertension (PH), the most severe form of autoimmune connective tissue disease.
Based on this, the main lines of research are: 1) Studying the autoimmune syndrome developed by P-selectin KO mice. The autoimmune syndrome developed by P-selectin KO mice will be analysed, along with its progression with age; we will also look at differences between the immune system of P-selectin and PSGL-1 KO mice in the blood, skin, lungs and kidneys to understand the different alterations found in these KO mice. Studies will also be carried out to determine whether bone marrow (BM) precursors from unmodified (WT) mice can prevent or reduce the symptoms of PSGL-1 KO and P-selectin KO, and whether BM precursors obtained from PSGL-1 KO and P-selectin KO can induce autoimmune syndrome in WT mice. 2) Study of the involvement of PSGL-1 and P-selectin in the development of PH.
The molecular mechanisms responsible for the development of PH will be studied, as well as alterations in the mitochondrial metabolism or in the levels of different molecules normally altered in PH patients, such as thrombospondin-1, angiotensin II and endothelin-1 and their receptors. 3) Involvement of PSGL-1 and its ligands ADAMS8, P-selectin, E-selectin and L-selectin in SSc, LES, mixed connective tissue disease and PH in humans. The levels of serum in these molecules will be analysed to find differences that may give rise to disease pathogenesis, and to asses their possible use as targets for diagnosis and/or prognosis. Immune system alterations and the involvement of PSGL-1 and P-selectin will also be investigated.
Ana Carmen Urzainqui Mayayo
Hospital Universitario La Princesa
| Other team members. Hospital Universitario La Princesa:
Urzainqui Mayayo, Ana Carmen. Immunoregulatory molecules as biomarkers predicting response to biological therapies and disease severity in immune-mediated inflammatory disorders. BIOMID PROJECT. PIE13/00041. ISCIII. Coordinated project. 2014-2016.
Urzainqui Mayayo, Ana Carmen. Study into the role of PSGL-1 in the control of the development of autoimmune diseases. Fundación Ramón Areces. 2012-2015.
Urzainqui Mayayo, Ana Carmen. PSGL-1/P-selectin interaction: homeostasis of the immune, vascular and reproductive systems in mice. Relevance of the development of PH and autoimmune diseases in humans. PI14/01698. ISCIII. 2015-2017.
Urzainqui Mayayo, Ana Carmen. Study into PSGL-1/P-selectin interaction and the signals induced in PH, scleroderma and lupus. Study into the molecular mechanisms altered in the absence of PSGL-1 or P-selectin. PI17/01819. ISCIII. 2018-2020.
Study into the implications of PSGL-1 and P-selectin on heart development in patients with pulmonary hypertension, scleroderma and lupus.
This grant is funded by the 2013-2016 Spanish Science, Technology and Innovation Research Plan and the ISCIII – Subdirectorate General for Evaluation and Promotion of Research – and co-financed by the European Regional Development Fund, Operational Programme Smart Growth 2014-2020 according to Regulation (EU) no. 1303/2013.
González-Tajuelo, Rafael, Silván, Javier, Pérez-Frías, Alicia, de la Fuente-Fernández, María, Tejedor, Reyes, Espartero-Santos, Marina, Vicente-Rabaneda, Esther, Juarranz, Ángeles, Muñoz-Calleja, Cecilia, Castañeda, Santos, Gamallo, Carlos, Urzainqui, Ana. “P-Selectin preserves immune tolerance in mice and is reduced in human cutaneous lupus”. Scientific Reports. 2017. 7: 41841. FI: 4,6 (Q1). PMID: 28150814. DOI: 10.1038/srep41841.
Silván, Javier, González-Tajuelo, Rafael, Vicente-Rabaneda, Esther, Pérez-Frías, Alicia, Espartero-Santos, Marina, Muñoz-Callejas Antonio, García Lorenzo, Elena, González-Alvaro, Isidoro, Gamallo, Carlos, Castañeda, Santos and Urzainqui, Ana. “Deregulated PSGL-1 expression in B cells and dendritic cells may be implicated in human systemic sclerosis development”. J Invest Dermatol. 2018. 138(10):2123-2132. FI: 6,5 (Q1). PMID: 29689251. DOI: 10.1016/j.jid.2018.04.003.
Pérez-Frías A, González-Tajuelo R, Núñez-Andrade N, Tejedor R, García-Blanco MJ, Vicente-Rabaneda E, Castañeda S, Gamallo C, Silván J, Esteban-Villafruela A, Cubero-Rueda L, García-García C, Muñoz-Calleja C, García-Diez A, Urzainqui A. Development of an Autoimmune Syndrome Affecting the Skin and Internal Organs in P-selectin Glycoprotein Ligand 1 Leukocyte Receptor-Deficient Mice. Arthritis Rheumatol 2014. 66: 3178-3189. FI: 0(Q4). PMID: 25132671. DOI: 10.1002/art.38808.
Nunez-Andrade, Norman, Lamana, Amalia, Sancho, David, Gisbert, Javier P., Gonzalez-Amaro, Roberto, Sanchez-Madrid, Francisco, Urzainqui, Ana. P-selectin glycoprotein ligand-1 modulates immune inflammatory responses in the enteric lamina propria. J Pathol 2011. 224: 212-221. FI: 6,318(Q1). PMID: 21432853. DOI: 10.1002/path.2850.
Dominguez-Luis, Maria, Lamana, Amalia, Vazquez, Jesus, Garcia-Navas, Rosula, Mollinedo, Faustino, Sanchez-Madrid, Francisco, Diaz-Gonzalez, Federico, Urzainqui, Ana. The metalloprotease ADAM8 is associated with and regulates the function of the adhesion receptor PSGL-1 through ERM proteins. Eur. J. Immunol. 2011. 41: 3436-3442. FI: 5,103(Q1). PMID: 22229154. DOI: 10.1002/eji.201141764.