Intracellular complement Factor B couples inflammatory sensing to metabolism, chromatin regulation and maladaptive tissue repair
Year: 2026
Type: preprint
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
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
Institutions: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, University Medical Center Hamburg-Eppendorf, Yale University, University Hospital Heidelberg, Purdue University West Lafayette, University of Arkansas for Medical Sciences, Purdue University Institute for Cancer Research, National Heart, Lung, and Blood Institute, Apellis Pharmaceuticals (United States), University of Virginia
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Health and Human Services, Deutsche Forschungsgemeinschaft, Universität Hamburg, National Institutes of Health, University of California, San Francisco, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1426378473, HPCCluster, G2457044174, G2924243443, G6425662989, G6909122442, Dissecting host-pathogen interactions through the lens of genomics, G8760597890, Unravelling immunoregulatory circuits of tissue inflammation, ChimeraX -- Next Generation Visualization and Analysis Software for Multiscale Modeling
OpenAlex ID: W7221450628