An unbiased map of FcγR signaling in neutrophils reveals druggable nodes in immune complex-mediated autoimmune disease
- 1Luebeck Institute of Experimental Dermatology (LIED), University of Luebeck, Luebeck, Germany
Abstract
Immune complexes drive tissue damage in autoimmune diseases through Fragment crystallizable {gamma} receptor (Fc{gamma}R) signaling, yet the underlying kinase networks are largely unexplored and treatment remains broadly immunosuppressive. We mapped signaling in immune complex-stimulated human neutrophils by combining an unbiased screen of 155 signal transduction inhibitors with multiplex kinase activity profiling, identifying 51 modulated kinases, 44 of them not previously linked to pemphigoid disease. Nine inhibitors, targeting PLC, PDK-1, PKC, DNA-PK, KSP, BTK, p38, c-Met and TBK-1, reduced neutrophil activity in vitro and disease severity in experimental epidermolysis bullosa acquisita, six of them after topical application. BTK emerged as a dominant node as inhibition with ibrutinib was effective therapeutically in immunization-induced disease, in mice reconstituted with a human immune system, and in models of arthritis and immune thrombocytopenia, the latter largely independent of neutrophils. These data provide a resource for Fc{gamma}R signaling in neutrophils and identify BTK as a cross-disease therapeutic target in antibody-mediated autoimmune disease.
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BibTeX
@misc{schlotfeldt2026unbiased,
title = {{An unbiased map of FcγR signaling in neutrophils reveals druggable nodes in immune complex-mediated autoimmune disease}},
author = {M. Schlotfeldt and C. Osterloh and A. Kasprick and C. Zünkeler and M. Armbrust and G. Kaiser and K. Schulze Dieckhoff and T. Mester and P. Stüssel and N. Ernst and A.-K. Schneider and L. Voss and A. P. Mansini and S. M. Vahabi and Y. F. Wang and H. Gainer and J. Li and G. Vidarsson and R. Visser and F. Petersen and X. Yu and K. T. Amber and A. Lux and R. J. Ludwig and K. Bieber},
howpublished = {bioRxiv},
year = {2026},
month = jul,
doi = {10.64898/2026.07.21.738176},
url = {https://www.biorxiv.org/content/10.64898/2026.07.21.738176v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - An unbiased map of FcγR signaling in neutrophils reveals druggable nodes in immune complex-mediated autoimmune disease
AU - M. Schlotfeldt
AU - C. Osterloh
AU - A. Kasprick
AU - C. Zünkeler
AU - M. Armbrust
AU - G. Kaiser
AU - K. Schulze Dieckhoff
AU - T. Mester
AU - P. Stüssel
AU - N. Ernst
AU - A.-K. Schneider
AU - L. Voss
AU - A. P. Mansini
AU - S. M. Vahabi
AU - Y. F. Wang
AU - H. Gainer
AU - J. Li
AU - G. Vidarsson
AU - R. Visser
AU - F. Petersen
AU - X. Yu
AU - K. T. Amber
AU - A. Lux
AU - R. J. Ludwig
AU - K. Bieber
PY - 2026
DA - 2026/07/21
PB - bioRxiv
DO - 10.64898/2026.07.21.738176
UR - https://www.biorxiv.org/content/10.64898/2026.07.21.738176v2
AB - Immune complexes drive tissue damage in autoimmune diseases through Fragment crystallizable {gamma} receptor (Fc{gamma}R) signaling, yet the underlying kinase networks are largely unexplored and treatment remains broadly immunosuppressive. We mapped signaling in immune complex-stimulated human neutrophils by combining an unbiased screen of 155 signal transduction inhibitors with multiplex kinase activity profiling, identifying 51 modulated kinases, 44 of them not previously linked to pemphigoid disease. Nine inhibitors, targeting PLC, PDK-1, PKC, DNA-PK, KSP, BTK, p38, c-Met and TBK-1, reduced neutrophil activity in vitro and disease severity in experimental epidermolysis bullosa acquisita, six of them after topical application. BTK emerged as a dominant node as inhibition with ibrutinib was effective therapeutically in immunization-induced disease, in mice reconstituted with a human immune system, and in models of arthritis and immune thrombocytopenia, the latter largely independent of neutrophils. These data provide a resource for Fc{gamma}R signaling in neutrophils and identify BTK as a cross-disease therapeutic target in antibody-mediated autoimmune disease.
ER -