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Analyses of Proteinuria, Renal Infiltration of Leukocytes, and Renal Deposition of Proteins in Lupus-prone MRL/lpr Mice
Published on: June 8, 2022
Damaged glomeruli in proliferative pediatric lupus nephritis exhibit a C5a-C5aR1 induced fibrotic transcriptional
Sarah McCuaig1, Easton Elliott1, Seth Anderson2
1Division of Rheumatology, Children's Hospital of Philadelphia, Philadelphia, PA.
Insights
Lupus nephritis involves kidney damage, but not from interferon. Instead, complement C5a signaling drives fibrosis in damaged glomeruli, offering new therapeutic targets for this condition.
Area of Science:
- Nephrology
- Immunology
- Genomics
Background:
- Lupus nephritis (LN) is a severe complication of pediatric systemic lupus erythematosus (pSLE), leading to poor kidney outcomes and treatment side effects.
- LN exhibits patchy glomerular damage within the same kidney, complicating understanding of injury drivers.
- Current understanding of LN pathogenesis lacks insight into localized glomerular injury mechanisms.
Purpose of the Study:
- To investigate microanatomic transcriptional differences between damaged and unaffected glomeruli in pSLE LN using spatial transcriptomics.
- To identify local drivers of renal injury in lupus nephritis.
- To explore the role of complement activation and fibrosis in LN pathogenesis.
Main Methods:
- Spatial transcriptomic analysis of glomeruli from pSLE LN patients to compare transcriptional profiles of damaged versus unaffected areas.
- Bulk RNA-sequencing of C5a-stimulated human monocyte-derived-macrophages.
- Analysis of complement component 5a (C5a) and its receptor C5aR1 signaling pathways.
Main Results:
- Glomerular damage in LN did not correlate with Type I interferon response, contrary to expectations for SLE.
- Transcriptional analysis revealed that damage was associated with myeloid cell markers, C5AR1 (receptor for C5a), early complement components, and fibrosis genes.
- C5a stimulation of macrophages upregulated tissue-remodeling and fibrosis pathways, which were reversed by avacopan, a C5aR1 inhibitor.
- Genes induced by C5a were significantly elevated in damaged LN glomeruli compared to unaffected ones, establishing a link between C5a-C5aR1 signaling and early fibrosis.
Conclusions:
- Complement C5a-C5aR1 signaling is a key driver of early fibrosis in proliferative lupus nephritis, independent of interferon response.
- This pathway represents a potential therapeutic target for lupus nephritis and other inflammatory diseases involving complement activation.
- The findings highlight an underappreciated link between complement activation and fibrotic processes in SLE.
Abstract:
Lupus nephritis (LN) is a leading cause of morbidity in pediatric systemic lupus erythematosus (pSLE) due to suboptimal kidney remission rates and the sequelae of prolonged intensive immunosuppressive therapy. LN is patchy, with some glomeruli severely damaged while others remain histologically unaffected in the same kidney. Using spatial transcriptomic technology, we interrogated microanatomic transcriptional differences between histologically damaged and unaffected glomeruli in pSLE LN to understand local drivers of renal injury. Despite SLE being a disease of Type I interferon (IFN), IFN gene response does not associate with local glomerular damage. Rather, damage associates with a transcriptional module of higher expression of myeloid cell markers, C5AR1 (encoding the receptor for complement component 5a [C5a]), early complement components, and fibrosis genes. Bulk RNA-sequencing of C5a stimulated human monocyte-derived-macrophages revealed upregulation of tissue-remodeling and fibrosis-related pathways reversible by the C5aR1 inhibiting drug avacopan. These same C5a-inducible fibrosis genes were significantly upregulated in histologically damaged versus unaffected LN glomeruli providing a mechanistic link between C5a-C5aR1 signaling and early fibrosis in proliferative lupus nephritis. Our data provide insight into an understudied connection between complement activation and fibrosis relevant in SLE and likely other inflammatory diseases of complement activation.
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