Development of a Highly Efficient Hybrid Peptide That Increases Immunomodulatory Activity Via the TLR4-Mediated Nuclear Factor-κB Signaling Pathway.

Lulu Zhang,Matthew Koci,Junhao Cheng,Xubiao Wei,Junyong Wang,Dayong Si,Rijun Zhang,Baseer Ahmad

doi:10.3390/ijms20246161

Abstract

Immunity is a defensive response that fights disease by identifying and destroying harmful substances or microbiological toxins. Several factors, including work-related stress, pollution, and immunosuppressive agents, contribute to low immunity and poor health. Native peptides, a new class of immunoregulatory agents, have the potential for treating immunodeficiencies, malignancies, and infections. However, the potential cytotoxicity and low immunoregulatory activity and stability of native peptides have prevented their development. Therefore, we designed three hybrid peptides (LTAa, LTAb, and LTAc) by combining a characteristic fragment of LL-37 with an active Tα1 center that included Tα1 (17–24), Tα1 (20–25), and Tα1 (20–27). The best hybrid peptide (LTAa), according to molecule docking and in vitro experiments, had improved immunoregulatory activity and stability with minimal cytotoxicity. We investigated the immunoregulatory effects and mechanisms of LTAa using a cyclophosphamide-immunosuppressed murine model. LTAa effectively reversed immunosuppression by enhancing immune organ development, activating peritoneal macrophage phagocytosis, regulating T lymphocyte subsets, and increasing cytokine (tumor necrosis factor-alpha, interleukin-6, and interleukin-1β) and immunoglobulin (IgA, IgG, and IgM) contents. The immunomodulatory effects of LTAa may be associated with binding to the TLR4/MD-2 complex and activation of the NF-κB signaling pathway. Therefore, LTAa could be an effective therapeutic agent for improving immune function.

Highlights

Immunity is a defensive response than can protect against disease by identifying and destroying harmful substances or microbiological toxins [1]
The structure model of the peptides using PyMOL software showed that all the hybrid peptides adopt an α-helix structure, which was verified by circular dichroism (CD) spectroscopy (Figure 1)
The results showed that all the hybrid peptides adopt an α-helix structure in 25 mM sodium dodecyl sulfate (SDS) and a random coil structure in water

Summary

Introduction

Immunity is a defensive response than can protect against disease by identifying and destroying harmful substances or microbiological toxins [1]. A suppressed immune system can make an organism more susceptible to infection, organ injury, and cancer [2], and immunity plays an important role in preventing and recovering from these immune-mediated diseases. Toll-like receptors (TLRs) are one of the pattern recognition receptors for conserved molecular patterns on microbial pathogens, and play important roles in host defense and in regulating immune responses [3]. The dimerization of TLR4/MD2 leads to the release of various proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-1β [7]. These cytokines are related to immune responses and have been implicated in host defense against pathogens [8]. TLR4/MD2 ligands are promising candidates as vaccine adjuvants and pharmaceuticals that support immunotherapies

Methods

Results

Discussion

Conclusion