Abstract
Summary
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-1β signals through IL-1R1 on injured tubular cells to recruit NF-κB 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.
Graphical abstract
Tissue injury induces coordinated C3-Factor B expression through myeloid IL-1β, IL-1R1, NF-κB and AP-1
Cytoplasmic FB regulates intracellular C3 processing, supporting mitochondrial respiratory adaptation to stress
Nuclear FB binds chromatin, promotes histone H3 processing and remodels promoter chromatin
The tubular C3-Factor B program promotes maladaptive repair and fibrosis, with key features conserved in human kidney disease