An unbiased map of FcγR signaling in neutrophils reveals druggable nodes in immune complex-mediated autoimmune disease

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.