Abstract
Inflammatory signals are broadly conserved, yet how tissue context converts them into programs of recovery or maladaptive repair remains unclear. Using kidney injury as a model of inflammation-to-repair transitions, we identify an injury-induced proximal-tubule complement program in which cell-intrinsic complement proteins are repurposed across subcellular compartments to couple inflammation to metabolic and chromatin regulation and promote maladaptive fibrotic remodeling. Mechanistically, myeloid-derived IL-1b; signals through IL-1R1 on injured tubular cells to recruit NF-kB and AP-1 to C3 and Cfb, coordinately inducing complement component 3 (C3) and Factor B (FB). Cytoplasmic FB drives cleavage-activation of cell-intrinsic C3, which supports tubular cell mitochondrial metabolic adaptation to stress and accumulation of C3aR-expressing macrophages around injured tubules. Nuclear FB, on the other hand, binds chromatin through a previously unrecognized DNA-binding interface and mediates histone H3 proteolysis and the preferential remodeling of chromatin promotors enriched in transcriptional programs relevant to maladaptive repair. Key features of this injury-associated C3-FB response, including intranuclear FB, are conserved in human kidney disease, associate with kidney dysfunction, and distinguish diseased from healthy kidneys. Together, these findings suggest that extracellular complement-targeting therapies may miss disease-relevant intracellular functions and suggest nuclear FB as a distinct target whose chromatin interaction and processing capacity could selectively limit maladaptive tissue responses beyond conventional inhibition.
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bioRxiv
The authors list and abstract were imported from bioRxiv on 12 Oct 2026.
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