Intracellular complement Factor B couples inflammatory sensing to metabolism, chromatin regulation and maladaptive tissue repair

Kidney injury provides insight into how inflammatory signals translate into programs of recovery or maladaptive repair. Researchers have discovered an injury-induced complement program within kidney proximal tubules that repurposes complement proteins across different cellular compartments to bridge inflammation and metabolic processes.

This process involves myeloid-derived IL-1b signaling through IL-1R1 on injured tubular cells, which recruits NF-kB and AP-1 to C3 and Cfb. The resulting activation of cytoplasmic Factor B (FB) facilitates the cleavage and activation of cell-intrinsic C3, promoting metabolic adaptation in tubular cells and the accumulation of C3aR-expressing macrophages around the damaged tissue.

Concurrently, nuclear FB binds chromatin via an unrecognized DNA-binding interface, mediating histone H3 proteolysis and preferential remodeling of chromatin promoters associated with maladaptive repair programs. The findings, which include intranuclear FB expression, are conserved in human kidney disease and correlate with kidney dysfunction, distinguishing diseased kidneys from healthy ones.

While conventional complement-targeting therapies might overlook these intracellular functions, the study highlights nuclear FB as a potential therapeutic target that could selectively mitigate maladaptive tissue responses.