Untangling the immunologic imbalance in SLE NET release 2434

Abstract Description The deposition of neutrophil extracellular traps (NETs) is thought to contribute nuclear antigens that exacerbate inflammation in the autoimmune disease systemic lupus erythematosus (SLE). We showed that mitochondrial lactate dehydrogenase (LDH) is essential to suicidal NET release (NETosis) in response to lactate producing microbes, like Staphylococcus aureus. However, SLE neutrophils do not undergo NETosis in response to S. aureus but instead undergo chronic vital NET release. We sought to determine the immunologic perturbations dysregulating neutrophil inflammation in SLE. Herein, we demonstrate that activation of TLR7 and TLR9 inhibit and TLR2 and TLR4 promote expression of LDHB, which is necessary to drive mitochondrial oxidative stress and suicidal NETosis in response to S. aureus. Furthermore, excessive type 1 interferon exacerbates vital NET release in response to S. aureus. As such, treating murine (MRL/lpr) and human SLE neutrophils with anifrolumab to inhibit the interferon alpha/beta receptor prevents chronic vital release, while inhibiting TLR7/9 signaling with hydroxychloroquine restores LDHB expression and suicidal NETosis in response to S. aureus. These findings decipher two of the immunologic perturbations dysregulating NETosis in SLE and indicate that NET release during SLE-related inflammation and in response to bacterial pathogens are two independent and possibly antagonistic processes. Funding Sources UTK Startup Funds NIH 1R35GM154838 Topic Categories Basic Autoimmunity (BA)