Dataset Information

Loss of CD11b Accelerates Lupus Nephritis in Lyn-Deficient Mice Without Disrupting Glomerular Leukocyte Trafficking.

ABSTRACT: Systemic lupus erythematosus (SLE) is a complex, heterogeneous autoimmune disease. A common manifestation, lupus nephritis, arises from immune complex deposition in the kidney microvasculature promoting leukocyte activation and infiltration, which triggers glomerular damage and renal dysfunction. CD11b is a leukocyte integrin mainly expressed on myeloid cells, and aside from its well-ascribed roles in leukocyte trafficking and phagocytosis, it can also suppress cytokine production and autoreactivity. Genome-wide association studies have identified loss-of-function polymorphisms in the CD11b-encoding gene ITGAM that are strongly associated with SLE and lupus nephritis; however, it is not known whether these polymorphisms act alone to induce disease or in concert with other risk alleles. Herein we show using Itgam^-/- mice that loss of CD11b led to mild inflammatory traits, which were insufficient to trigger autoimmunity or glomerulonephritis. However, deficiency of CD11b in autoimmune-prone Lyn-deficient mice (Lyn^-/-Itgam^-/- ) accelerated lupus-like disease, driving early-onset immune cell dysregulation, autoantibody production and glomerulonephritis, impacting survival. Migration of leukocytes to the kidney in Lyn^-/- mice was unhindered by lack of CD11b. Indeed, kidney inflammatory macrophages were further enriched, neutrophil retention in glomerular capillaries was increased and kidney inflammatory cytokine responses were enhanced in Lyn^-/-Itgam^-/- mice. These findings indicate that ITGAM is a non-monogenic autoimmune susceptibility gene, with loss of functional CD11b exacerbating disease without impeding glomerular leukocyte trafficking when in conjunction with other pre-disposing genetic mutations. This highlights a primarily protective role for CD11b in restraining inflammation and autoimmune disease and provides a potential therapeutic avenue for lupus treatment.

SUBMITTER: Gottschalk TA

PROVIDER: S-EPMC9134083 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Loss of CD11b Accelerates Lupus Nephritis in Lyn-Deficient Mice Without Disrupting Glomerular Leukocyte Trafficking.

Gottschalk Timothy A TA Hall Pamela P Tsantikos Evelyn E L'Estrange-Stranieri Elan E Hickey Michael J MJ Hibbs Margaret L ML

Frontiers in immunology 20220512

Systemic lupus erythematosus (SLE) is a complex, heterogeneous autoimmune disease. A common manifestation, lupus nephritis, arises from immune complex deposition in the kidney microvasculature promoting leukocyte activation and infiltration, which triggers glomerular damage and renal dysfunction. CD11b is a leukocyte integrin mainly expressed on myeloid cells, and aside from its well-ascribed roles in leukocyte trafficking and phagocytosis, it can also suppress cytokine production and autoreacti ...[more]

PMID: 35634296

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Project description:IntroductionLupus nephritis (LN) is a major risk factor of morbidity and mortality. Glomerular injury is associated with different pathogeneses and clinical presentations in LN patients. However, the molecular mechanisms involved are not well understood. This study aimed to explore the molecular characteristics and mechanisms of this disease using bioinformatics analysis.MethodsTo characterize glomeruli in LN, microarray datasets GSE113342 and GSE32591 were downloaded from the Gene Expression Omnibus database and analyzed to determine the differentially expressed genes (DEGs) between LN glomeruli and normal glomeruli. Functional enrichment analyses and protein-protein interaction network analyses were then performed. Module analysis was performed using the Search Tool for the Retrieval of Interacting Genes/Proteins and Cytoscape software. Immunofluorescence staining was performed to identify the glomerular expression of S100A8 in various International Society of Nephrology/Renal Pathology Society (ISN/RPS) class LN patients. The image of each glomerulus was acquired using a digital imaging system, and the green fluorescence intensity was quantified using Image-Pro Plus software.ResultsA total of 13 DEGs, consisting of 12 downregulated genes and one upregulated gene (S100A8), were identified in the microarray datasets. The functions and pathways associated with the DEGs mainly include inflammatory response, innate immune response, neutrophil chemotaxis, leukocyte migration, cell adhesion, cell-cell signaling, and infection. We also found that monocytes and activated natural killer cells were upregulated in both GSE113342 and GSE32591. Glomerular S100A8 staining was significantly enhanced compared to that in the controls, especially in class IV.ConclusionsThe DEGs identified in the present study help us understand the underlying molecular mechanisms of LN. Our results show that glomerular S100A8 expression varies in different pathological types; however, further research is required to confirm the role of S100A8 in LN.

Dataset Information

Loss of CD11b Accelerates Lupus Nephritis in Lyn-Deficient Mice Without Disrupting Glomerular Leukocyte Trafficking.

Publications

Loss of CD11b Accelerates Lupus Nephritis in Lyn-Deficient Mice Without Disrupting Glomerular Leukocyte Trafficking.

Similar Datasets

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