Negative regulation of signaling by a soluble form of toll-like receptor 9

Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA.
European Journal of Immunology (Impact Factor: 4.03). 08/2011; 41(8):2176-84. DOI: 10.1002/eji.201041034
Source: PubMed


Nucleic acid structures are highly conserved through evolution and when self nucleic acids are aberrantly detected by toll-like receptors (TLRs) they contribute to autoimmune disease. For this reason, multiple regulatory mechanisms exist to prevent immune responses to self nucleic acids. TLR9 is a nucleic acid-sensing TLR that is regulated at multiple levels including association with accessory proteins, intracellular localization and proteolytic processing. In the endolysosomal compartment TLR9 is proteolytically processed to an 80 kDa form (p80) and this processing is a prerequisite for activation. Here, we identified a soluble form of TLR9 (sTLR9) generated by a novel proteolytic event that cleaved TLR9 between amino acids 724-735. Similar to p80, sTLR9 was generated in endosomes. However, generation of sTLR9 was independent of the cysteine protease cathepsin B, active at acidic pH, but partially dependent on cathepsin S, a protease active at neutral pH. Most importantly, sTLR9 inhibited TLR9-dependent signaling. Altogether, these data support a model where an intrinsic proteolytic processing mechanism negatively regulates TLR9 signaling. A proper balance between the independent proteolytic events probabably contributes to regulation of TLR9-mediated innate immunity and prevention of autoimmune disease.

Download full-text


Available from: Cynthia A Leifer, Mar 26, 2015
13 Reads
  • Source
    • "ST2 (known as IL-33 receptor), single immunoglobulin IL-1R-related molecule (SIGGR/TIR8), and RP105 (a homolog of TLR4, essential for LPS recognition with MD-1 in B cells) negatively regulate TLR signaling at their receptor levels (Liew et al., 2005). A soluble form of TLR9 generated by the cleavage of TLR9 between amino acids 724–735 inhibits TLR9-dependent signaling (Chockalingam et al., 2011). An adaptor molecule, Toll/IL-1R resistance motif containing protein (SARM) localized in mitochondria, inhibits both MyD88 and TRIF-dependent pathways (Belinda et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Toll-like receptors (TLRs) are pattern recognition receptors that distinguish conserved microbial products, also known as pathogen-associated molecular patterns (PAMPs), from host molecules. Liver is the first filter organ between the gastrointestinal tracts and the rest of the body through portal circulation. Thus, the liver is a major organ that must deal with PAMPs and microorganisms translocated from the intestine and to respond to the damage associated molecular patterns (DAMPs) released from injured organs. These PAMPs and DAMPs preferentially activate TLR signaling on various cell types in the liver inducing the production of inflammatory and fibrogenic cytokines that initiate and prolong liver inflammation, thereby leading to fibrosis. We summarize recent findings on the role of TLRs, ligands, and intracellular signaling in the pathophysiology of liver fibrosis due to different etiology, as well as to highlight the potential role of TLR signaling in liver fibrosis associated with hepatitis C infection, non-alcoholic and alcoholic steatoheoatitis, primary biliary cirrhosis, and cystic fibrosis.
    Frontiers in Physiology 05/2012; 3:138. DOI:10.3389/fphys.2012.00138 · 3.53 Impact Factor
  • Source
    • "Once nucleic acid-sensing TLRs do reach endosomes, they are proteolytically processed (Chockalingam, et al. 2011; Ewald, et al. 2008; Park, et al. 2008), which modifies their function. Cleavage at two different locations within the ectodomain leads to either activation (Ewald, et al. 2008; Park, et al. 2008), or inhibition (Chockalingam, et al. 2011), of TLR9 activity. Specific identification of the enzymes responsible for these proteolytic events will provide new targets for drug development to interfere with TLR signaling and response to host DNA. "
    Systemic Lupus Erythematosus, 03/2012; , ISBN: 978-953-51-0266-3
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Intracellular TLRs sense viral and bacterial nucleic acids from a wide variety of pathogens. Previous studies have shown that TLR9 requires processing for signalling. Following proteolysis, a fragment corresponding to the C-terminal part of TLR9 was shown to bind MyD88 and to induce signalling when cells were stimulated with TLR9 ligands. In this issue of the European Journal of Immunology, a study provides evidence that another proteolytic fragment of TLR9 is generated, different to that described previously, consisting of amino acids 1-723 which mediates inhibition of TLR9 signalling. These results suggest that proteolysis undoubtedly is a key step in TLR9 regulation.
    European Journal of Immunology 08/2011; 41(8):2142-4. DOI:10.1002/eji.201141858 · 4.03 Impact Factor
Show more