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.
Show 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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