Figure 1: Self-amplifying feed-forward loops of NETosis in SLE.
In SLE patients, NETosis can be triggered by anti-LL37 or HNP autoantibodies or RNP/anti-RNP immune complexes with subsequent engagement of TLR7. A subset of SLE patients failed to clear NETs due to the DNase I inhibitory components in the serum (such as NET-associated anti-NET Abs, LL37 or C1q). NETs are taken up by pDC in an FcRIIa and TLR9 dependent manner, leading to the release of IFNα. IFNα in turn can prime neutrophils for enhanced NETosis by upregulating TLR7 and surface granular proteins (such as LL37 and HNP). IFN also triggers autoreactive T and B cell activation, resulting in the production of anti-NET Abs, such as anti-dsDNA, anti-LL37, and anti-HNP Abs. NETs and LL37 alone can activate the NLRP3 inflammasome in macrophages to induce the synthesis of IL-1β and IL-18, both of which can stimulate NETosis. Those pathogenic loops may eventually lead to an imbalanced immune homeostasis that contributes to the disease initiation and progression of SLE.
Abbreviations: SLE: Systemic Lupus Erythematosus; FcRIIa: Immunoglobulin- Fc region receptor II-a; RNP: Ribonucleoprotein; Ab: Antibody; TLR: Toll-like Receptor; NET: Neutrophil Extracellular Traps; DNase: Deoxyribonuclease; pDC: Plasmacytoid Dendritic Cell; IFN: Interferon; HNP: Human Neutrophil Peptide; NLRP3: NOD-like receptor, pyrin domain containing-3; IL: Interleukin.