Development of an Autoimmune Syndrome Affecting the Skin and Internal Organs in P‐Selectin Glycoprotein Ligand 1 Leukocyte Receptor–Deficient Mice

Abstract

Objective. To define and characterize the progression of the spontaneous autoimmune disease that develops in mice in the absence of the leukocyte adhesion receptor P-selectin glycoprotein ligand 1 (PSGL-1).Methods. Skin-resident immune cells from PSGL-1-deficient mice and C57BL/6 control mice of different ages were isolated and analyzed by flow cytometry. Biochemical parameters were analyzed in mouse 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 from PSGL-1 ؊/؊ mice had a proinflammatory phenotype with an imbalanced T effector cell:Treg cell ratio. Sera from PSGL-1 ؊/؊ mice had circulating autoantibodies commonly detected in connective tissuerelated human autoimmune diseases. Biochemical and histologic analysis of skin and internal organs revealed skin fibrosis and structural and functional abnormalities in the lungs and kidneys. Furthermore, PSGL-1 ؊/؊ mice exhibited vascular alterations, showing loss of dermal vessels, small vessel medial layer remodeling in the lungs and kidneys, and ischemic processes in the kidney that promote renal infarcts.Conclusion. Our study demonstrates that immune system overactivation 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.

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

“…Given the elevated rate of death in PSGL‐1 −/− mice after reaching 1 year of age , echocardiography was used to measure the PAAT:ET ratio (Figure A), an indirect evaluation of pulmonary pressure. Since preliminary data suggested differences in the PAAT:ET ratio between WT and PSGL‐1 −/− mice, follow‐up transthoracic Doppler echocardiography was performed on WT and PSGL‐1 −/− littermates between 1.5 and 18 months of age.…”

“…The PSGL‐1–P‐selectin interaction triggers a tolerogenic program in human monocyte‐derived dendritic cells, which drive Treg cell generation . Accordingly, disease exacerbation has been described in PSGL‐1–deficient (PSGL‐1 −/− ) mice in different experimental inflammatory models . More importantly, PSGL‐1 −/− mice progressively develop an autoimmune syndrome which shares multiple features with human SSc, such as autoantibody production, dermal fibrosis, and vascular damage .…”

PSGL-1: A New Player in the Immune Checkpoint Landscape

“…These findings indicate that PSGL-1 expression on Tregs supports their suppressive capacity to inhibit effector T cells. Interestingly, one report showed that Selplg −/− mice had increased numbers of T cell effectors producing IFN-γ, IL-4, and IL-17 in skin, corresponding to Th1, Th2, and Th17 populations, but no differences in Tregs [86]. This spontaneous autoimmune phenotype was not reported in other studies [23, 67, 70] indicating that potential microbiota and/or strain differences may modulate effector responses in Selplg −/− animals.…”

Deregulated PSGL-1 Expression in B Cells and Dendritic Cells May Be Implicated in Human Systemic Sclerosis Development

“…The leukocyte receptor PSGL-1 is the major ligand for the cell adhesion molecule P-selectin and mediates the initial contacts with endothelial cells during their extravasation (Carlow et al, 2009). Additionally, PSGL-1/P-selectin interactions contribute to generate regulatory T cells (Urzainqui et al, 2007), and deficiency in either component not only increases the severity of several inflammatory diseases in animal models, such as collagen-induced arthritis in P-selectineknockout mice or dextran sulfate sodium-induced colitis in PSGL-1eknockout mice (Bullard et al, 1999;Nuñ ez-Andrade et al, 2011) but also leads to the spontaneous development of an autoimmune disease resembling human lupus or SSc, respectively (González-Tajuelo et al, 2017;Pérez-Frías et al, 2014). PSGL-1 is proteolytically processed by the metalloproteinase ADAM8, which may represent a regulatory mechanism to govern the expression of PSGL-1 on leukocyte membranes (Domínguez-Luis et al, 2011).…”