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.
Highlights
Systemic lupus erythematosus (SLE) is a chronic, multi-faceted autoimmune disease that usually manifests in various organs [1]
The therapeutic efficacy of TLR inhibitor peptide 1 (TIP1) was evaluated in MRL/lpr mouse, a well-known model of SLE characterized with high levels of circulating antibodies and inflammatory cytokines that develop an autoimmune disease similar to human SLE [22]
To evaluate its therapeutic potential, TIP1 was administered to B6J and MRL/lpr mice
Summary
Systemic lupus erythematosus (SLE) is a chronic, multi-faceted autoimmune disease that usually manifests in various organs [1]. SLE-related immunomodulatory abnormalities induce overproduction of autoantibodies such as anti-nuclear antibodies (ANA) and antidsDNA antibodies, as well as immune complexes, and stimulate complement activation. While the exact cause of SLE is still unknown, genetic variation and environmental factors are thought be plausible factors [4,5]. Various genetic variations observed in patients with lupus, including Ets-1, have recently been identified, and immune profiling has been performed [6,7]. A combination of genetic defects and environmental factors such as hormones, ultraviolet light, drugs, and infections forces the immune system to fail to recognize the “self” and begin to attack cells and destroy various organs, leading to SLE [8]
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