Background Innate immunity cells, cytokines and inflammatory pathways have been recognised as inducers and amplifiers of autoimmune responses and tissue injury in SLE.
Methods Published experimental data during the last five years on the contribution of innate immunity, particularly neutrophils and type I interferon, are summarized and their clinical implications are discussed.
Results Recent genome-wide expression studies have implicated neutrophils in human SLE and lupus nephritis. Through a combined transcriptomic, epigenetic, and functional analysis, distinct subtypes of these cells have been identified in patients with SLE, with low-density granulocytes exhibiting excessive death by generation of extracellular chromatin traps (NETs) that are decorated with immunostimulatory/alarmin molecules such as interleukin-33 and promote the activation of other immune cells, type I interferon (IFN) production and endothelial injury. Intracellular protein citrullination mediated by neutrophil peptidylarginine deiminases (PADs) is critical for NETs formation and accordingly, targeting PADs ameliorates lupus disease by reducing autoantibodies, type I IFN, immune cell activation, vascular dysfunction, and NET immunogenicity. Notably, activation of Toll-like receptors (TLR)-7/8 in neutrophils causes proteolytic cleavage of the N-terminal part of Fc-γ-receptors (FcgrIIA), thus abrogating their capacity to phagocytose immunocomplexes while promoting their death by NETosis.
Mechanistically, recruitment of syntenin-1 by UNC93B1 has been reported to facilitate the sorting of TLR-7 into multivesicular bodies, therefore offering dynamic regulation of TLR-7 activation/signaling. Besides NETs, a number of other pathways may enhance IFN production in SLE such as apoptosis-derived membrane vesicles through activation of cGAS–STING, and photosensitivity-induced IFN-kappa released by keratinocytes. The latter is in line with clinical observations that therapeutic blockade of IFN or downstream signaling may be particularly beneficial in cutaneous manifestations of SLE. Remarkably, IFN signature is present in multiple immune cell types in SLE such as in B-cells where it causes breach of tolerance, promoting autoreactive B cell development into the autoantibody-forming cell and germinal center pathways. In T-cells, SLE patients who carry the STAT4 risk allele rs7574865[t] display augmented inflammatory responses to IL-12 and IFN-α, and vice versa, IFN-α may augment the IL-12-induced STAT4 activation, therefore highlighting a subgroup of patients who may benefit from IFNa/JAK/STATs targeting.
Conclusions Culminating research further supports the critical role of neutrophils and innate immune pathways in SLE pathogenesis. Elucidation of intracellular pathways pertaining to production and regulation of important mediators such as IFN may provide novel insights towards development of targeted therapies.
Acknowledgements This work was supported by Special Research Account of the University of Crete (grant no. 4718).
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