Toll-like Receptor Signaling Inhibitory Peptide Improves Inflammation in Animal Model and Human Systemic Lupus Erythematosus

Abstract

Toll-like receptors (TLRs) play a major role in the innate immune system. Several studies have shown the regulatory effects of TLR-mediated pathways on immune and inflammatory diseases. Dysregulated functions of TLRs within the endosomal compartment, including TLR7/9 trafficking, may cause systemic lupus erythematosus (SLE). TLR signaling pathways are fine-tuned by Toll/interleukin-1 receptor (TIR) domain-containing adapters, leading to interferon (IFN)-α production. This study describes a TLR inhibitor peptide 1 (TIP1) that primarily suppresses the downstream signaling mediated by TIR domain-containing adapters in an animal model of lupus and patients with SLE. The expression of most downstream proteins of the TLR7/9/myeloid differentiation factor 88 (MyD88)/IFN regulatory factor 7 signaling was downregulated in major tissues such as the kidney, spleen, and lymph nodes of treated mice. Furthermore, the pathological analysis of the kidney tissue confirmed that TIP1 could improve inflammation in MRL/lpr mice. TIP1 treatment downregulated many downstream proteins associated with TLR signaling, such as MyD88, interleukin-1 receptor-associated kinase, tumor necrosis factor receptor-associated factor 6, and IFN-α, in the peripheral blood mononuclear cells of patients with SLE. In conclusion, our data suggest that TIP1 can serve as a potential candidate for the treatment of SLE.

Novel neoplasms associated with syndromic pediatric medulloblastoma: integrated pathway delineation for personalized therapy

“…MYD88 encodes a cytosolic adaptor protein involved in the innate and adaptive immune responses downstream of Toll-like receptors [ 25 ], and the D210N mutation maps to the TIR (Toll/Interleukin-1 Receptor) domain. Although its role in the pituitary adenoma pathogenesis is speculative at this time, it may be related to the presence of inflammatory infiltrates in this tumor [ 26 ]. The M6 MB showed a clonal XRCC3 p.G107* truncating mutation with LOH, and a subclonal ERBB3 p.V83E VUS in the extracellular domain of the receptor tyrosine kinase (RTK).…”

Identification of NETs-related biomarkers and molecular clusters in systemic lupus erythematosus

“…The toll-like receptors (TLRs) respond to molecular patterns associated with microbes such as bacteria and viruses, stimulating innate and acquired immunity as well as an inflammatory response and cytokines upregulation ( 58 ). Several studies suggest that the signaling pathway has essential activity in the pathogenesis of autoimmune diseases including SLE ( 59 , 60 ). Therefore, we speculate that CREB5 may participate in the pathogenesis of SLE with the involvement of PI3K-Akt and Toll-like receptor signaling pathways and serve as a potential therapeutic target.…”

Role of PIN1 in human pathology: Cellular regulation, pathogenesis and therapeutic implications (Review)

“…SLE is a systemic, debilitating autoimmune disease with a variety of clinical manifestations affecting multiple organs in the body (64). The Toll-like receptor 7 (TLR-7)/TLR-9/interleukin (IL)-1 receptor-associated kinase 1 (IRAK-1)/interferon regulatory factor 7 (IRF-7) pathway plays a key role in the development and progression of SLE (65)(66)(67). Furthermore, it has been observed that PIN1 activity is upregulated upon the activation of TLR7 or TLR9 and interacts with IRAK1 in primary dendritic cells.…”