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.

Qualitative Proteome-wide Lysine Crotonylation Profiling Reveals Protein Modification Alteration in the Leukocyte Extravasation Pathway in Systemic Lupus Erythematosus

“…On the basis of FC ≥ 1.20 or ≤1/1.2, 417 hyper-crotonylated lysine sites for 184 hyper-crotonylated proteins and 275 hypo-crotonylated sites for 150 proteins were identified between SLE patients and normal control individuals (Figure 2A). Mostly DMPs are located in the cytoplasm (114) according to subcellular localization analysis and distributed at the nucleus (31), extracellular (29), mitochondria (24), or plasma membrane (16) (Figure 2B). Among 272 dyscrotonylated proteins, most proteins (199) contained 1 or 2 dyscrotonylation sites, and 12.1% of DMPs (33) had more than 5 dyscrotonylation sites (Figure 2C).…”

“…Leukocytes, which circulate in the blood, trigger inflammatory reactions by migrating from the bloodstream to injured tissues. The function of leukocytes in SLE has previously been established, and its dysfunction may lead to inflammatory cytokine response enhancement and autoimmune disorders . The inflamed tissue releases chemokines, which promotes leukocytes adhering and transmigrating across vascular endothelial cells (VECs) and then reaching the extravascular space. , In the inflammatory site, endothelial cells express IL-8, switching the leukocyte integrins LFA-1 and VLA-4 to affinitive states, then encouraging leukocytes to move from rolling to adhesion and migration .…”

Removal of the endothelial surface layer via hyaluronidase does not modulate monocyte and neutrophil interactions with the glomerular endothelium

“…Glomerular leukocyte trafficking was assessed by MP‐IVM of either intact kidneys or post‐hydronephrotic kidneys as previously described 3,37,38 . The rationale for utilizing both intact and post‐hydronephrotic kidneys was based on our previous studies of glomerular leukocyte trafficking associated with acute inflammation which have consistently demonstrated comparable results using these two methods 1,3,4,39,40 .…”

“…Glomerular leukocyte trafficking was assessed by MP‐IVM of either intact kidneys or post‐hydronephrotic kidneys as previously described. 3 , 37 , 38 The rationale for utilizing both intact and post‐hydronephrotic kidneys was based on our previous studies of glomerular leukocyte trafficking associated with acute inflammation which have consistently demonstrated comparable results using these two methods. 1 , 3 , 4 , 39 , 40 Given these results, in this study, intact and post‐hydronephrotic kidneys were used in parallel to address the experimental aims, with the proviso that comparisons between experimental groups were made only between kidneys prepared in the same manner.…”

CD11b suppresses TLR7-driven inflammatory signaling to protect against lupus nephritis

“…4a). CD11b KO animals, prone to autoimmune disease [69], exhibitied worsened splenomegaly and splenic CD11b + leukocyte expansion compared to WT mice (Figs. 4b-4c).…”