Arthritis Rheumatol. 2014 Nov;66(11):3178-89. doi: 10.1002/art.38808.

Development of an autoimmune syndrome affecting the skin and internal organs in P-selectin glycoprotein ligand 1 leukocyte receptor-deficient mice.

Pérez-Frías A1#, González-Tajuelo R1#, Núñez-Andrade N1, Tejedor R2, García-Blanco MJ1, Vicente-Rabaneda E3, Castañeda S3, Gamallo C4, Silván J1, Esteban-Villafruela A1, Cubero-Rueda L1, García-García C5, Muñoz-Calleja C2, García-Diez A5, Urzainqui A.

#Both authors have contributed equally to this work

 Fundación de Investigación Biomédica, Instituto de Investigación Sanitaria-Princesa (IIS-Princesa), Hospital de la Princesa, C/ Diego de León 62, 28006-Madrid, Spain.

1Immunology Department, 2Cytometry and Autoimmunity Unit, 3Rheumatology Department, 4Pathology Department, 5Dermatology Department.

Corresponding author:

Ana Urzainqui, Ph.D.


Telephone Number: +(34)915202307

Fax Number: +(34)915202374


Grants/Financial supporters:

Spanish Ministry of Health (Grant Nº.FIS-PI080894, and FIS-PI11-01418)

Fundación Ramón Areces (Grant 2012-2015)



Objectives To define and characterize the progression of the spontaneous autoimmune disease developed in mice in the absence of the leukocyte adhesion receptor PSGL-1.

Methods PSGL-1-deficient mice and C57Bl/6 control mice were sacrificed at different ages. Skin-resident immune cells were isolated and analyzed by flow cytometry. Biochemical parameters were analyzed in serum and urine and the presence of serum autoantibodies was investigated. Skin and internal organs were extracted and their structure was analyzed histologically.

Results Skin-resident innate and adaptive immune cells of PSGL-1-/- mice have a pro-inflammatory phenotype with an imbalanced Teff/Treg ratio. Sera from PSGL-1-/- mice present circulating autoantibodies commonly detected in connective tissue-related human autoimmune diseases. Biochemical and histological analysis of skin and internal organs reveal skin fibrosis and structural and functional abnormalities in lungs and kidneys. Furthermore, PSGL-1-/- mice exhibit vascular alterations, showing loss of dermal vessels, small vessel medial layer remodeling in lung and kidney and ischemic processes in the kidney that promote renal infarcts.

Conclusions Our study demonstrates that immune system over-activation due to PSGL-1 deficiency triggers an autoimmune syndrome with characteristics similar to systemic sclerosis, including skin fibrosis, vascular alterations and systemic organ involvement. These results suggest that PSGL-1 expression contributes to the maintenance of the homeostasis of the immune system and could act as a barrier for autoimmunity in mice.

PMID: 25132671



PSGL-1 is an adhesion receptor expressed by all leukocyte subtypes. PSGL-1 interaction with P-selectin is responsible for the tethering and rolling of leukocytes on the endothelial cells previous to their extravasation to the inflamed tissue but also during the homeostatic homing and entry into different tissues and organs, including the skin, bone marrow and thymus. We had previously demonstrated that PSGL-1 acts as a tolerogenic receptor in human monocyte-derived dendritic cells and contributes to maintain the tolerance in the colonic lamina propria in mice (Núñez-Andrade et al., 2011)

au fig1In this study, we describe that the absence of PSGL-1 in mice breaks down self-tolerance and induce the development of an autoimmune syndrome that has characteristics similar to human systemic sclerosis. One of the first signs of the disease, observed at early age in PSGL-1 deficient mice (PSGL-1-/-), is skin fibrosis (Fig. 1) together with the presence of circulating autoantibodies (Fig. 2). In addition, PSGL-1-/- mice have a reduced number of dermal vessels and a thickened the medial layer of the small vessels in the kidneys and lungs, indicating vascular alterations, the other hallmark of SSc (Fig. 3). With ageing, the affection of internal organs increases and hence, aged PSGL-1-/- mice have non-specific interstitial pneumonia, present a high rate of renal infarcts and show a high mortality rate during the second year of life, indicating that PSGL-1 could be an important molecule in the pathogenesis of this disease. Importantly, none of the current mouse models with skin fibrosis fulfill criteria of human systemic sclerosis. Conversely, PSGL-1-/- mice exhibit the three hallmarks of human scleroderma: skin fibrosis, vascular damage and autoimmunity, and constitute the first mouse model which completely mimics human systemic sclerosis. PSGL-1-/- mice represent an invaluable tool to understand the pathogenesis of the disease and to check new therapeutic approaches in preclinical assays.



Nuñez-Andrade N, Lamana A, Sancho D, Gisbert JP, Gonzalez-Amaro R, Sanchez-Madrid F, Urzainqui A. “P-selectin glycoprotein ligand-1 modulates immune inflammatory responses in the enteric lamina propria”. J Pathol. 2011 Jun;224(2):212-21. doi: 10.1002/path.2850. Epub 2011 Mar 22. PMID: 21432853



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