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

Authors

Tilo Freiwald, Daniel Chauss, Md Tajmul, Jorge Luis Trujillo-Ochoa, Dhaneshwar Kumar, Jianping Ma, Madeline A Snyder, Nardos T Cheru, Julius Fe Jaeger, Yuxin Zhuang, Justin B Gregor, Akshatha Ganne, Luopin Wang, Yubing Guo, Maja Gunkel, Tobias B Huber, Thorsten Wiech, Erin E West, Srinivas Ayyadevara, Martin Kolev, Scott D Briggs, Claudia Kemper, Majid Kazemian, Didier Portilla, Behdad Afzali

Published in

bioRxiv : the preprint server for biology. Oct 11, 2026. Epub Oct 11, 2026.

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-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.
Tissue injury induces coordinated C3-Factor B expression through myeloid IL-1β, IL-1R1, NF-κB and AP-1Cytoplasmic FB regulates intracellular C3 processing, supporting mitochondrial respiratory adaptation to stressNuclear FB binds chromatin, promotes histone H3 processing and remodels promoter chromatinThe tubular C3-Factor B program promotes maladaptive repair and fibrosis, with key features conserved in human kidney disease.

PMID:
42926470
Bibliographic data and abstract were imported from PubMed on 25 Oct 2026.

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