Grupo 56 – IIS PRINCESA

P-selectin glycoprotein ligand 1 (PSGL-1) is a leukocyte receptor that interacts with P-, E-, and L-selectins and is responsible for the initial steps of leukocyte extravasation to sites of inflammation. Our laboratory has shown that PSGL-1 acts as an immunoregulatory receptor involved in the generation of regulatory T cells (Tregs) and contributes to the maintenance of peripheral tolerance in mice. We have demonstrated that PSGL-1 knockout (KO) mice develop a progressive autoimmune disease similar to systemic sclerosis (SSc) (Pérez-Frías et al., Arthritis and Rheumatology, 2014). Furthermore, we observed that the absence of P-selectin, the primary ligand of PSGL-1, causes an autoimmune syndrome similar to systemic lupus erythematosus (SLE), with the generation of anti-dsDNA autoantibodies, immune complex deposits in the skin and kidneys, and hypersensitivity to ultraviolet light—features that could correspond to SLE (González-Tajuelo et al., Scientific Reports, 2017). Interestingly, we recently reported that aged P-selectin and PSGL-1 knockout (KO) females develop pulmonary arterial hypertension (PAH)—the most severe form of connective tissue-related autoimmune diseases—due to increased angiotensin II levels and endothelial dysfunction, with low nitric oxide production (NO) (González-Tajuelo et al., Arthritis and Rheumatology, 2019). Notably, clinical studies in patients indicate that the expression of PSGL-1 and P-selectin is altered in both diseases. Patients with SSc exhibit reduced PSGL-1 expression in B lymphocytes and increased expression in monocytes, dendritic cells, and T lymphocytes. Furthermore, our data show an association between elevated PSGL-1 expression and the presence of diffuse interstitial lung disease (ILD) in patients with SSc, and that presence of more than 75% of circulating plasmacytoid dendritic cells (pDCs) expressing ADAM8 are associated with the presence of SSc (Silván J et al., J Invest Dermatol, 2018). In patients with lupus, a reduction in P-selectin expression in cutaneous vessels and a decrease in PSGL-1 expression in neutrophils and monocytes have been observed, correlating with disease activity. Importantly, recent research has demonstrated the role of PSGL-1/P-selectin in regulating apoptosis in neutrophils and monocytes, as well as in the generation of NETs and METs, and its dysregulation in patients with SLE (Muñoz-Callejas et al., IJMS, 2023; Muñoz-Callejas et al., Translational Research, 2024). Furthermore, we have identified biomarkers for the differential diagnosis of SSc and SLE (San Antonio et al., Front Immunol, 2024). In light of these findings, our primary objective is to study the molecular and cellular alterations underlying the pathology of these diseases.

Main lines of research

Study of interstitial pneumonia associated with scleroderma (SSc-ILD) and lupus (SLE-ILD), one of the leading causes of mortality in these diseases. Analysis of cells and molecular components involved in the development of ILD, with the aim of identifying molecular alterations that may serve as potential diagnostic biomarkers or therapeutic targets. Validation of biomarkers identified in our laboratory for the differential diagnosis of systemic sclerosis, systemic lupus erythematosus, and primary Sjögren’s syndrome and evaluation of these biomarkers to help in the early diagnosis. Analysis of PSGL-1 as a potential regulator of cellular proteostasis and its contribution to the pathology of scleroderma and SLE.

Jefe de grupo:

Dra. Ana Carmen Urzainqui Mayayo
- Antonio Muñoz Callejas
- Alejandra Ramos Manzano
- María Esther San Antonio Sánchez
- Inés Sánchez Abad
- Javier Silván Montoya