Type I IFN–dependent FcγRIV signaling in murine monocytes promotes lethal anaphylaxis during viral infections
Abdelrahman Elwy, Hossam Abdelrahman, Julia Specht, Gina M. Ewert, Justa Friebus-Kardash, Swati Dhiman, Julia Falkenstein, Theresa Charlotte Christ, Elisa Wiebeck, Arzoo Shamoon, Nils B. Leimkühler, Thomas Gramberg, Alina Russ, Ulrich Kalinke, Fei Kuang, Kathrin Sutter, Manfred Kopf, Matthias Mack, Wiebke Hansen, Falk Nimmerjahn, Karl S. Lang
Abdelrahman Elwy, Hossam Abdelrahman, Julia Specht, Gina M. Ewert, Justa Friebus-Kardash, Swati Dhiman, Julia Falkenstein, Theresa Charlotte Christ, Elisa Wiebeck, Arzoo Shamoon, Nils B. Leimkühler, Thomas Gramberg, Alina Russ, Ulrich Kalinke, Fei Kuang, Kathrin Sutter, Manfred Kopf, Matthias Mack, Wiebke Hansen, Falk Nimmerjahn, Karl S. Lang
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Research Article Autoimmunity Immunology Infectious disease

Type I IFN–dependent FcγRIV signaling in murine monocytes promotes lethal anaphylaxis during viral infections

Abstract

Anaphylaxis is a life-threatening hypersensitivity reaction. Clinical observations suggest heightened susceptibility during viral infections, yet the mechanisms remain poorly defined. Here, we show that both active and passive IgG-mediated anaphylaxis were exacerbated in the setting of acute viral infection. In mice, this enhancement was driven predominantly by FcγRIV, the homolog of human FcγRIIIa. FcγRIV crosslinking induced anaphylactic symptoms selectively in infected animals, with no effect in naive conditions. Among leukocytes, inflammatory monocytes emerged as the principal drivers of this lethal reaction. Viral infection triggered a strong upregulation of FcγRIV on inflammatory monocytes, an effect absent in type I IFN receptor–deficient (Ifnar1-deficient) mice. Extending these findings, we observed increased frequencies of CD16-expressing classical monocytes in patients with acute COVID-19, and murine SARS-CoV-2 infection recapitulated this phenotype. Mechanistically, FcγRIV crosslinking during infection promoted the production of platelet-activating factor, the key mediator of mortality, in a type I IFN–dependent (IFN-I–dependent) manner. Together, these findings indicate that viral infection creates an immune milieu that heightens monocyte sensitivity to Fcγ receptor engagement, positioning these cells as major effectors of IgG-mediated hypersensitivity in the infected host. They further suggest that Fc receptor pathway modulation merits further investigation in contexts with heightened IFN-I responses, such as in systemic lupus erythematosus.

Authors

Abdelrahman Elwy, Hossam Abdelrahman, Julia Specht, Gina M. Ewert, Justa Friebus-Kardash, Swati Dhiman, Julia Falkenstein, Theresa Charlotte Christ, Elisa Wiebeck, Arzoo Shamoon, Nils B. Leimkühler, Thomas Gramberg, Alina Russ, Ulrich Kalinke, Fei Kuang, Kathrin Sutter, Manfred Kopf, Matthias Mack, Wiebke Hansen, Falk Nimmerjahn, Karl S. Lang

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Figure 5

IFN-I signaling is crucial for FcγRIV upregulation on inflammatory monocytes.

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IFN-I signaling is crucial for FcγRIV upregulation on inflammatory monoc...
(A) IHC images of splenic tissue from naive and LCMV-infected WT, Fcgr4–/–, and Ifnar1–/– mice 24 h.p.i. Representative images from 3 independent experiments (n = 2–3 mice/group/experiment). Scale bars: 100 μm. (B) MFI quantification of FcγRIV in spleen sections of naive and LCMV-infected WT and Ifnar1–/– mice (n = 2–3 mice/group/experiment; data were pooled from 2–3 experiments). (C) Geometric mean fluorescence intensity (gMFI) of the FcγRIV expression on neutrophils (CD11b+Ly6G+), patrolling monocytes (mo.) (CD11b+Ly6C–CD43+FcγRIV+), and inflammatory monocytes (CD11b+Ly6Chi). Monocyte subsets were gated from negative lineages (Ly6G–CD3–CD19–) in blood, as were macrophages in spleens from naive and LCMV-infected WT and Ifnar1–/– mice (1 × 106 PFU) (24 h.p.i.). Data were pooled from 2 (naive) or 3 (infected) experiments (n = 3 mice/group/experiment). (D) Quantification of FcγRIV+Ly6Chi inflammatory monocytes in the blood and spleen of naive and LCMV-infected (1 × 106 PFU) WT and Ifnar1–/– mice 24 h.p.i. Data were pooled from 2 independent experiments (n = 3 mice/group/experiment). (E) Bone marrow inflammatory monocytes from WT and Ifnar1–/– mice were treated for 18 hours with varying IFN-β concentrations. Histograms and gMFI quantification are shown. Data are shown from 2 of 3 independent experiments; all experiments produced similar results (n = 2 mice/group/experiment). Data are presented as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA.