Limits...
Toll-like receptors: potential targets for lupus treatment.

Wu YW, Tang W, Zuo JP - Acta Pharmacol. Sin. (2015)

Bottom Line: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the loss of tolerance to self-nuclear antigens.Accumulating evidence shows that Toll-like receptors (TLRs), previously proven to be critical for host defense, are implicated in the pathogenesis of autoimmune diseases by recognition of self-molecules.A number of downstream proteins in the TLR signaling cascade (such as MyD88, IRAKs and IFN-α) are identified as potential therapeutic targets for SLE treatment.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

ABSTRACT
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the loss of tolerance to self-nuclear antigens. Accumulating evidence shows that Toll-like receptors (TLRs), previously proven to be critical for host defense, are implicated in the pathogenesis of autoimmune diseases by recognition of self-molecules. Genome-wide association studies, experimental mouse models and clinical sample studies have provided evidence for the involvement of TLRs, including TLR2/4, TLR5, TLR3 and TLR7/8/9, in SLE pathogenesis. A number of downstream proteins in the TLR signaling cascade (such as MyD88, IRAKs and IFN-α) are identified as potential therapeutic targets for SLE treatment. Numerous antagonists targeting TLR signaling, including oligonucleotides, small molecular inhibitors and antibodies, are currently under preclinical studies or clinical trials for SLE treatment. Moreover, the emerging new manipulation of TLR signaling by microRNA (miRNA) regulation shows promise for the future treatment of SLE.

Show MeSH

Related in: MedlinePlus

Potential targets involved in TLR signaling pathways for SLE treatment. TLR-mediated responses are controlled mainly in a MyD88-dependent way, which is used by all TLRs except TLR3. In the pathogenesis of SLE, both exogenous ligands from infection and endogenous ligands from apoptotic debris contribute to the activation of TLRs and initiate the downstream signaling cascade, resulting in the production of type I IFN and inflammatory cytokines. A series of potential therapeutics, including oligonucleotides, SMIs and antibodies, modulate TLR signaling pathways at different stages. Some oligonucleotides, SMIs and TLR-neutralized antibodies directly block TLRs; some SMIs target TLR accessory proteins, such as MyD88 and IRAKs. Anti-IFN-α antibodies are also under intensive development for the treatment of SLE. TAK1, transforming growth factor-β-activated kinase; IRF, interferon regulatory factor.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4816237&req=5

fig1: Potential targets involved in TLR signaling pathways for SLE treatment. TLR-mediated responses are controlled mainly in a MyD88-dependent way, which is used by all TLRs except TLR3. In the pathogenesis of SLE, both exogenous ligands from infection and endogenous ligands from apoptotic debris contribute to the activation of TLRs and initiate the downstream signaling cascade, resulting in the production of type I IFN and inflammatory cytokines. A series of potential therapeutics, including oligonucleotides, SMIs and antibodies, modulate TLR signaling pathways at different stages. Some oligonucleotides, SMIs and TLR-neutralized antibodies directly block TLRs; some SMIs target TLR accessory proteins, such as MyD88 and IRAKs. Anti-IFN-α antibodies are also under intensive development for the treatment of SLE. TAK1, transforming growth factor-β-activated kinase; IRF, interferon regulatory factor.

Mentions: Currently, there are diverse agents under development for lupus treatment by targeting TLRs or TLR accessory proteins (including MyD88, IRAK-4 and IFN-α) at different stages of TLR signaling pathways (Figure 1). Here, we focus on a series of agents in the discovery phase or in clinical trials, including oligonucleotides (Table 1), small molecular inhibitors (SMIs) (Table 2), antibodies (Table 3) and new emerging modulators, such as microRNAs, which might offer further possibilities for therapeutic manipulation.


Toll-like receptors: potential targets for lupus treatment.

Wu YW, Tang W, Zuo JP - Acta Pharmacol. Sin. (2015)

Potential targets involved in TLR signaling pathways for SLE treatment. TLR-mediated responses are controlled mainly in a MyD88-dependent way, which is used by all TLRs except TLR3. In the pathogenesis of SLE, both exogenous ligands from infection and endogenous ligands from apoptotic debris contribute to the activation of TLRs and initiate the downstream signaling cascade, resulting in the production of type I IFN and inflammatory cytokines. A series of potential therapeutics, including oligonucleotides, SMIs and antibodies, modulate TLR signaling pathways at different stages. Some oligonucleotides, SMIs and TLR-neutralized antibodies directly block TLRs; some SMIs target TLR accessory proteins, such as MyD88 and IRAKs. Anti-IFN-α antibodies are also under intensive development for the treatment of SLE. TAK1, transforming growth factor-β-activated kinase; IRF, interferon regulatory factor.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4816237&req=5

fig1: Potential targets involved in TLR signaling pathways for SLE treatment. TLR-mediated responses are controlled mainly in a MyD88-dependent way, which is used by all TLRs except TLR3. In the pathogenesis of SLE, both exogenous ligands from infection and endogenous ligands from apoptotic debris contribute to the activation of TLRs and initiate the downstream signaling cascade, resulting in the production of type I IFN and inflammatory cytokines. A series of potential therapeutics, including oligonucleotides, SMIs and antibodies, modulate TLR signaling pathways at different stages. Some oligonucleotides, SMIs and TLR-neutralized antibodies directly block TLRs; some SMIs target TLR accessory proteins, such as MyD88 and IRAKs. Anti-IFN-α antibodies are also under intensive development for the treatment of SLE. TAK1, transforming growth factor-β-activated kinase; IRF, interferon regulatory factor.
Mentions: Currently, there are diverse agents under development for lupus treatment by targeting TLRs or TLR accessory proteins (including MyD88, IRAK-4 and IFN-α) at different stages of TLR signaling pathways (Figure 1). Here, we focus on a series of agents in the discovery phase or in clinical trials, including oligonucleotides (Table 1), small molecular inhibitors (SMIs) (Table 2), antibodies (Table 3) and new emerging modulators, such as microRNAs, which might offer further possibilities for therapeutic manipulation.

Bottom Line: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the loss of tolerance to self-nuclear antigens.Accumulating evidence shows that Toll-like receptors (TLRs), previously proven to be critical for host defense, are implicated in the pathogenesis of autoimmune diseases by recognition of self-molecules.A number of downstream proteins in the TLR signaling cascade (such as MyD88, IRAKs and IFN-α) are identified as potential therapeutic targets for SLE treatment.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

ABSTRACT
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the loss of tolerance to self-nuclear antigens. Accumulating evidence shows that Toll-like receptors (TLRs), previously proven to be critical for host defense, are implicated in the pathogenesis of autoimmune diseases by recognition of self-molecules. Genome-wide association studies, experimental mouse models and clinical sample studies have provided evidence for the involvement of TLRs, including TLR2/4, TLR5, TLR3 and TLR7/8/9, in SLE pathogenesis. A number of downstream proteins in the TLR signaling cascade (such as MyD88, IRAKs and IFN-α) are identified as potential therapeutic targets for SLE treatment. Numerous antagonists targeting TLR signaling, including oligonucleotides, small molecular inhibitors and antibodies, are currently under preclinical studies or clinical trials for SLE treatment. Moreover, the emerging new manipulation of TLR signaling by microRNA (miRNA) regulation shows promise for the future treatment of SLE.

Show MeSH
Related in: MedlinePlus