Table 1.
Negative regulators of Toll-like receptor (TLR) signaling with their mechanism of action and relevance to disease
| Negative regulators | Mode of action | Diseases implicated | Reference(s) |
|---|---|---|---|
| Regulators of ligand binding | |||
| sTLR2 (soluble form of TLR2) | Prevents lipopeptide binding to TLR2 through competitive binding | In human milk sTLR2 protects infants from enterocolitis and sepsis | 139 |
| sTLR4 (soluble form of TLR4) | Prevents LPS binding to TLR4 through competitive binding | Elevated levels of sTLR4 are found in human endotoxemia and auto-inflammatory syndromes | 140 |
| sCD14 (soluble CD14) also known as presepsin | Diverts LPS from membrane-bound CD14 and promotes LPS efflux from cell-surface CD14 | Marker of inflammatory diseases and sepsis | 141, 142 |
| RP105 (radioprotective 105) | RP105-MD1 complex binds to TLR4-MD2 complex and prevents LPS binding | Increased expression in primary biliary cirrhosis | 25, 143 |
| Triad3A | E3 ubiquitin-protein ligase that enhances ubiquitination and degradation of TLR4 and TLR9 | Overexpression reported in diabetic kidneys | 144, 145 |
| Regulators of adaptor complexes | |||
| SARM (sterile alpha and armadillo motif-containing molecule) | Negatively regulates TRIF-dependent TLR signaling and MyD88-mediated AP-1 activation | May mediate endotoxin tolerance | 146 |
| Splicing variant of MyD88 (MyD88s) | Splice form is unable to activate NF-κB | None | 27 |
| TAG | Splice variant of TRAM, negatively regulates MyD88-independent TLR4 pathway | None | 28 |
| ST2 (single immunoglobulin IL-1R-related molecule) ST2L: membrane bound ST2: soluble form |
Prevents the recruitment of MyD88 and TIRAP (MAL) to TLR2, -4, and -6 by sequestering them | Prevents renal epithelial immunity in diabetes | 145, 147 |
| TRAF1 (TNF receptor-associated factor) | Inhibits TLR3 mediated NF-κB activation and IFN-β signaling by interacting with TRIF | TRAF1 polymorphisms are associated with autoimmune thyroid disease | 148, 149 |
| TRAF4 | Physically interacts and functionally counteracts with TRAF6 and TRIF | Implicated in human IBD | 150, 151 |
| Cbl-b (casitas B-lineage lymphoma, an E3 ubiquitin ligase) | Mediates ubiquitination of MyD88 and TRIF | Causes dysregulation of macrophage activation in obesity-induced insulin resistance | 152, 153 |
| CYLD (deubiquitinase) | By deubiquitinating K63-linked polyubiquitination of MyD88, a form required for TLR signaling | Brooke-Spiegler syndrome | 154, 155 |
| SOCS1 | Phosphorylated TIRAP (MAL) is bound to SOCS1 which results in TIRAP polyubiquitination and degradation | Psoriasis, MS, viral infections, and many others | 156 |
| Regulators of signaling molecules | |||
| Splicing variants of IRAK1 (IRAK1c), IRAK2 (IRAK2c, 2d) | Splice forms were unable to activate NF-κB | None | 157, 158 |
| IRAKM | Lacks intrinsic kinase activity and hence prevents dissociation of IRAK4 and IRAK1 from MyD88 | IRAKM+22148 G>A allele associated with risk of developing chronic relapsing pouchitis | 159, 160 |
| SHP-1 and SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase-1 and -2) | SHP-1 suppresses IRAK1 and IRAK2 activities and SHP-2 negatively regulates TRIF-dependent type I IFN production | Leishmania spp. promote SHP-1 binding to IRAK1 to suppress innate response | 161, 162 |
| SIGIRR (single immunoglobulin interleukin-1 receptor-related) | Interacts with and blocks the activation of IRAKs and TRAF6 | SLE, dominant negative forms reported in human colon tumors | 163 |
| A20 (deubiquitinase) | Deubiquitinates TRAF6 and prevents its binding to TAK1 and subsequent Iκκ complex formation | TNFAIP3 gene (that codes for A20) polymorphisms are reported in RA, SLE, psoriasis, Crohn’s disease, and other autoinflammatory diseases | 30, 164 |
| β-Arrestin 2 | Interacts with TRAF6 and prevents its oligomerizationNegatively regulates TLR4 signaling by targeting p38 MAPK and IL-10; regulates TLR4-mediated apoptotic signaling through GSK3α | Several fibrotic diseases | 165, 166 |
| TRIM38 (tripartite-motif containing 38) | Binds to TRAF6 and promotes K48-linked polyubiquitination, and proteasomal degradation | Primary Sjögren’s syndrome | 167, 168 |
| Lyp (lymphocyte tyrosine phosphatase) | Potentiates type I IFN from TLR signaling through interaction with TRAF3 and promoting its K63 ubiquitination | SNP in PTPN22 gene that encodes Lyp results in autoimmune risk allele (Lyp620W) and hence associated with several autoimmune diseases | 169 |
| TRIM30α (tripartite-motif containing −30α) | Negatively regulates NF-κB activation by targeting TAB2 and TAB3 for degradation | DSS-induced colitis mouse model | 170 |
| Regulators of transcription factors | |||
| ATF3 (activating transcription factor 3; a member of ATF/DREB family) | Restrict access to NF-κB and AP-1 to the promoter regions of proinflammatory cytokines IL-6 and IL-12b | Type 2 diabetes, cardiac hypertrophy, osteoarthritis | 35, 171 |
| NOD2 | NOD2 signaling inhibits TLR2 driven activation of NF-κB subunit c-Rel | Crohn’s disease, sarcoidosis | 172, 173 |
| PI3K | Suppresses p38 MAPK and NF-κB through PKB; PI3K can also directly inhibit IL-12 production | E.g., fibrosis, diabetes, COPD, IBD, RA, SLE, MS | 10, 174 |
| Pin1 (peptidyl prolyl isomerase) | Mediates ubiquitination and subsequent proteasome-dependent degradation of IRF3 | Overexpressed in several cancers; implicated in allergic pulmonary inflammation | 175, 176 |
| IRF4 | Competitively inhibits IRF5 binding to TLR | SLE | 177, 178 |
| RAUL (RTA-associated ubiquitin ligase) | Catalyzes ubiquitination of IRF3/7 and negatively regulates type I IFN responses | Kaposi sarcoma herpes virus stabilizes RAUL by preventing its degradation and thereby downmodulating antiviral response | 179 |
Abbreviations: COPD, chronic obstructive pulmonary disease; DSS, dextran sulfate sodium; IBD, inflammatory bowel disease; IFN, interferon; IRF, interferon regulatory factor; LPS, lipopolysaccharide; MAL, MyD88 adapter-like; MS, multiple sclerosis; PKB, protein kinase B; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphism; TAG, TRAM adaptor with GOLD domain; TIRAP, Toll-like receptor adaptor protein.