S100A8/A9 (Calprotectin) Is Critical for Development of Glomerulonephritis and Promotes Inflammatory Leukocyte–Renal Cell Interactions

Abstract

Glomerulonephritis is a common cause of end-stage renal disease. Infiltrating leukocytes interacting with renal cells play a critical role during the initiation and progression of glomerulonephritis, but the exact mechanisms are not clearly defined. By using the murine model of nephrotoxic nephritis, we investigated the role of S100A8/A9 [myeloid-related protein (MRP) 8/14, calprotectin] in promoting glomerulonephritis. In nephrotoxic nephritis, wild-type (WT) mice with glomerulonephritis have elevated serum levels of S100A8/A9, whereas mice deficient in MRP14 (S100a9(-/-)), and hence S100A8/A9, are significantly protected from disease. By using bone marrow transplants, we showed that MRP14 deficiency is required in both the hemopoietic and intrinsic cells for the protective effect. In vitro, both the WT bone marrow-derived macrophages and renal mesangial cells stimulated with S100A8/A9 secrete IL-6, CXCL1, and tumor necrosis factor α; however, Mrp14(-/-) cells exhibit significantly blunted proinflammatory responses. The interaction of WT bone marrow-derived macrophages with renal microvascular endothelial cells results in increased levels of monocyte chemotactic protein 1, IL-8, and IL-6 cytokines, which is attenuated in Mrp14(-/-) bone marrow-derived macrophages. Data shows that S100A8/A9 plays a critical role during glomerulonephritis, exerting and amplifying autocrine and paracrine proinflammatory effects on bone marrow-derived macrophages, renal endothelial cells, and mesangial cells. Therefore, complete S100A8/A9 blockade may be a new therapeutic target in glomerulonephritis.

The role of monocytes in ANCA-associated vasculitides

“…Serum levels of calprotectin are raised in active AAV and remained elevated after treatment in patients that relapse [39]. Consistent with this observation, it has recently been demonstrated in an animal model of nephrotoxic nephritis that calprotectin may induce renal injury through its effects on macrophages [40].…”

“…Pro-inflammatory stimuli promote calprotectin translocation to the cellular membrane and its systemic release from neutrophils, monocytes and early macrophages. In turn, calprotectin induces cytokine and chemokine release, and tissue damage, generating an autocrine inflammatory response [40]. Serum levels of calprotectin are raised in active AAV and remained elevated after treatment in patients that relapse [39].…”

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

“…6). In addition, we observed a >10-fold renal induction in s100A9, a neutrophilic mediator associated with kidney damage 35 , as well as increased s100A6 expression, a calcium-binding protein associated with tubular injury 36 . (Fig.…”

Effects of unsaturated fatty acids (Arachidonic/Oleic Acids) on stability and structural properties of Calprotectin using molecular docking and molecular dynamics simulation approach

“…The human S100A8/A9 complex has the molecular weight of 11 and 13 kDa with 93 and 114 amino acids respectively [7,8]. Various configurations of the S100A8/A9 complex are available including homodimers, heterodimers and heterotetramers which the heterodimer form has the highest stability and it is the most important agent for protein interactions [5,9,10]. Due to absence of signal peptide sequence in the aforementioned complex, the protein secretion is done via an energy dependent PKC-activation procedure, not by endoplasmic reticulum-Golgi pathway [4,11,12].…”