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

• Published in: International journal of molecular sciences Vol. 22; no. 23; p. 12764
• Main Authors: Baek, Wook-Young, Choi, Yang-Seon, Lee, Sang-Won, Son, In-Ok, Jeon, Ki-Woong, Choi, Sang-Dun, Suh, Chang-Hee
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25.11.2021; MDPI
• Subjects: Adapter proteins; Adapters; Animal models; Animals; Antibodies; Autoimmune diseases; Chronic conditions; Cytokines; Disease; Disease Models, Animal; Domains; Gene Expression Regulation; Humans; Immune system; inbred MRL/lpr; Inflammation; Inflammation - etiology; Inflammation - metabolism; Inflammation - pathology; Inflammation - prevention & control; Inflammatory diseases; Innate immunity; Interferon; Interleukin 1; Kidneys; Kinases; Leukocytes (mononuclear); Lupus; lupus erythematosus; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - etiology; Lupus Erythematosus, Systemic - metabolism; Lupus Erythematosus, Systemic - pathology; Lymph nodes; Lymphatic system; Lymphocyte Activation; Male; Mice; Mice, Inbred MRL lpr; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Pathogens; Patients; Peptide Fragments - pharmacology; Peptides; Peripheral blood mononuclear cells; Phosphorylation; Protein expression; Proteins; Signal transduction; Spleen; systemic; Systemic lupus erythematosus; TLR7 protein; Toll-like receptors; Toll-Like Receptors - antagonists & inhibitors; Urine; α-Interferon; Toll-like receptors; inbred MRL/lpr; systemic; lupus erythematosus; mice
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222312764

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/ 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.