AAV-caused Kidney Involvement Is Linked to Immune Monocyte Cells
Similar to neutrophils, immune monocyte cells play an essential role in kidney damage caused by ANCA-associated vasculitis (AAV), a study discovered.
The pro-inflammatory function of monocytes was stimulated by the immune signaling protein CSF2, also called GM-CSF.
Therapeutically targeting monocytes or CSF2 may be a potential new treatment strategy to prevent or slow kidney failure in people with AVV, the scientists suggested.
Details of the discovery were published in the Annals of the Rheumatic Diseases, in the study, “CSF2-dependent monocyte education in the pathogenesis of ANCA-induced glomerulonephritis.”
In AAV, self-reactive antibodies called anti-neutrophil cytoplasmic antibodies, or ANCAs, mistakenly target one of two proteins — proteinase 3 or myeloperoxidase (MPO) — found in immune cells called neutrophils.
This overly activates the cells, causing inflammation and damage to small blood vessels, including those in the kidneys.
Monocytes are a type of immune cell also overly activated by ANCAs, but unlike neutrophils, monocytes’ role in AAV remains unclear.
Researchers in Germany evaluated the effects of suppressing classical and nonclassical monocytes in a mouse model of anti-MPO AAV.
Classical monocytes are critical for initial inflammatory responses, while nonclassical monocytes, derived from classical monocytes, patrol the bloodstream seeking out blood vessel damage.
The researchers first looked at glomerulonephritis in mice lacking either CD22, a receptor protein necessary for monocyte activation, or C/EBP-beta, a molecule essential for nonclassical monocyte development and survival.
Glomerulonephritis is a common AAV symptom marked by inflammation in the blood vessel network that filters waste from the kidneys, which impairs their function and can progress to kidney failure.
Mice lacking CD22 showed significantly fewer classical monocytes in kidney tissue and were protected from glomerulonephritis. Blood and protein in urine samples were also significantly lower in these animals.
“These experiments firmly establish the central role of [classical monocytes] in mediating anti-MPO-induced [glomerulonephritis],” the team wrote.
In contrast, mice with and without C/EBP-beta showed equal signs of kidney damage and blood and protein in their urine, suggesting this type of monocyte does not participate in glomerulonephritis.
Next, the research team investigated the potential role of CSF2 in AAV. CSF2 is a key pro-inflammatory molecule involved in developing several inflammatory and autoimmune disorders. It was previously found at markedly higher levels in patients with active AAV compared with those in remission or healthy people.
Mice with anti-MPO AAV-like disease showed significantly higher CSF2 levels in kidney tissue and urine relative to healthy mice in whom the pro-inflammatory molecule was undetectable in these samples.
At the same time, the activity of the gene that encodes for CSF2 was strongly increased in kidney tissue, and higher CSF2 levels were significantly associated with more kidney damage.
Mice depleted from the CSF2 receptor were protected from kidney injury, showing that CSF2’s interaction with its receptor is essential for kidney damage. In addition, treating glomerulonephritis-induced normal mice with an anti-CSF2 antibody attenuated kidney damage development.
Experiments to understand the underlying mechanism showed CSF2 stimulated the excess release of the potent pro-inflammatory signaling protein interleukin-1-beta from monocytes. CSF2 was also associated with stimulating immune T-cells to produce interleukin-17A, an important contributor to kidney injury in AAV.
“Together, these data establish that CSF2 increases pro-inflammatory monocyte functions,” the researchers wrote.
An examination of kidney tissue biopsied from patients with active AAV showed a marked increase in CSF2 levels in infiltrating immune cells and significantly higher urine CSF2 levels compared with healthy controls.
The research team also analyzed the urine of 31 AAV patients with active disease involving the kidneys, 20 patients with stable AAV but previous kidney involvement, and eight healthy controls. Those with active AVV-related kidney disease had a significantly higher classical monocyte count relative to the other two groups.
These findings “provide a mechanistic explanation how monocytes contribute to [blood vessel inflammation] and the subsequent kidney damage,” the researchers wrote, and established CSF2’s role in the “activation of monocytes and subsequent regulation of T cells” in AAV.
“Our results may encourage future studies exploring CSF2 and its receptor interaction as a potential therapeutic target in AAV, particularly since compounds targeting either CSF2 or its receptor are currently tested in clinical trials,” the researchers concluded.
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