A TLR7/9-IFNα-LDHB axis drives vital NET release and compromises antibacterial defense.

TenBarge, E. G.; Wise, A. D.; Hetzel, M. L.; Hoover, H. A.; Esfandiari, H.; Holder, B. E.; Belevska, E.; Mennen, E. C.; McDaniel, S. R.; Vaccaro, N. M.; Lucca, C. C.; Williams, J. M.; Ferris, J.; Sparer, T. E.; Crofford, L. J.; Bieber, J. D.; Monteith, A. J.

doi:10.1101/2025.10.07.680928

bioRxiv · 10.1101/2025.10.07.680928

A TLR7/9-IFNα-LDHB axis drives vital NET release and compromises antibacterial defense.

TenBarge, E. G.·Wise, A. D.·Hetzel, M. L.·Hoover, H. A.·Esfandiari, H.·Holder, B. E.·Belevska, E.·Mennen, E. C.·McDaniel, S. R.·Vaccaro, N. M.·Lucca, C. C.·Williams, J. M.·Ferris, J.·Sparer, T. E.·Crofford, L. J.·Bieber, J. D.·Monteith, A. J.

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Abstract

Patients with systemic lupus erythematosus (SLE) are susceptible to bacterial infections, but the underlying dysfunction remains unclear. We found that Staphylococcus aureus triggers mitochondria-dependent suicidal NETosis via lactate sensing in healthy neutrophils, but this response is defective in SLE. Herein, we show that chronic Toll-like receptor (TLR) 7/9 signaling represses mitochondrial lactate dehydrogenase B (LDHB), thereby impairing lactate sensing and downstream suicidal NETosis. Instead, SLE neutrophils default to vital NET release; a less bactericidal, type I interferon (IFN)-driven process amplified by staphylococcal pore-forming toxins and sustained by elevated systemic IFN levels observed in SLE. Combined treatment with hydroxychloroquine (HCQ) and interferon-alpha/beta receptor (IFNAR) blockade restores LDHB expression, NET homeostasis, and bacterial clearance in lupus-prone mice. Neutrophils from SLE patients exhibit similar defects, which are reversed by HCQ and the IFNAR-blocking antibody anifrolumab. These findings identify a clinically actionable immunometabolic checkpoint linking chronic autoimmune signaling to defective antibacterial defense in SLE.

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TenBarge, E. G., Wise, A. D., Hetzel, M. L., Hoover, H. A., Esfandiari, H., Holder, B. E., Belevska, E., Mennen, E. C., McDaniel, S. R., Vaccaro, N. M., Lucca, C. C., Williams, J. M., Ferris, J., Sparer, T. E., Crofford, L. J., Bieber, J. D., Monteith, A. J.. 2025-10-07. A TLR7/9-IFNα-LDHB axis drives vital NET release and compromises antibacterial defense.. https://doi.org/10.1101/2025.10.07.680928

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