Damaged glomeruli in proliferative pediatric lupus nephritis exhibit a C5a-C5aR1 induced fibrotic transcriptional program

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.