Taking the STING out of TLR-driven autoimmune diseases: good, bad, or indifferent?

Abstract

Both endosomal and cytosolic-nucleic acid-sensing receptors can detect endogenous ligands and promote autoimmunity and autoinflammation. These responses involve a complex interplay among and between the cytosolic and endosomal sensors involving both hematopoietic and radioresistant cells. Cytosolic sensors directly promote inflammatory responses through the production of type I IFNs and proinflammatory cytokines. Inflammation-associated tissue damage can further promote autoimmune responses indirectly, as receptor-mediated internalization of the resulting cell debris can activate endosomal Toll-like receptors (TLR). Both endosomal and cytosolic receptors can also negatively regulate inflammatory responses. A better understanding of the factors and pathways that promote and constrain autoimmune diseases will have important implications for the development of agonists and antagonists that modulate these pathways.

Wiskott-Aldrich syndrome protein restricts cGAS/STING activation by dsDNA immune complexes

“…Notably, administration of STING inhibitors in vivo rescued chronic transcription of Isg15 in the spleen of WASp-null animals, indicat- ing that chronic systemic activation by circulating endogenous inducers depends on cytosolic sensing and can be modulated by inhibiting this pathway. Thus, as has been shown in monogenic disorders and in complex systemic diseases (4,5,(36)(37)(38), cytoskeletal defects can impact the threshold of self-NA sensing.…”

USP38 Couples Histone Ubiquitination and Methylation via KDM5B to Resolve Inflammation

“…[3,4] Although inflammation is important for the initiation of protective immunity, dysregulated inflammation can lead to tissue destruction, autoimmune disease, and tumor progression owing to the excessive production of proinflammatory cytokines. [5][6][7][8] Therefore, the inflammatory response must be tightly regulated. Inflammation could be induced and controlled by the regulation of PRR-mediated signaling networks, which involves the transcription factor nuclear factor-B (NF-B) signaling and inflammasome pathway.…”

“…[ 3,4 ] Although inflammation is important for the initiation of protective immunity, dysregulated inflammation can lead to tissue destruction, autoimmune disease, and tumor progression owing to the excessive production of proinflammatory cytokines. [ 5–8 ] Therefore, the inflammatory response must be tightly regulated.…”

Epstein-Barr virus infection as a predisposing factor for multiple sclerosis. An update from molecular biology, immunology and epidemiology

“…In this way, the immune system can initiate and perpetuate the inflammatory response against autoantigens by cross-reacting with viral antigens (molecular mimicry) and residues of cellular and viral metabolism. (33)(34)(35) Flow cytometry and realtime PCR have demonstrated that viral RNA transcripts (EBER-1 and express viral proteins corresponding to type II latency. Thanks to the type 0 latency proteins, infected B cell reach circulation and undergo negative regulation by EBV to evade the immune response.…”