Resistin, a Novel Host Defense Peptide of Innate Immunity

Abstract

Resistin, a cysteine-rich protein, expressed in adipocytes, was initially proposed as a link between obesity and diabetes in mice. In humans, resistin is considered to be a pro-inflammatory molecule expressed in immune cells, which plays a regulatory role in many chronic inflammatory diseases, metabolic diseases, infectious diseases, and cancers. However, increasing evidence shows that resistin functions as a host defense peptide of innate immunity, in terms of its wide-spectrum anti-microbial activity, modulation of immunity, and limitation of microbial product-induced inflammation. To date, the understanding of resistin participating in host defense mechanism is still limited. The review aims to summarize current knowledge about the biological properties, functions, and related mechanisms of resistin in host defense, which provides new insights into the pleiotropic biological function of resistin and yields promising strategies for developing new antimicrobial therapeutic agents.

Keywords: anti-bacteria; anti-inflammation; host defense peptide; immunomodulation; innate immunity; resistin.

Figure 1

Trimeric structure of human resistin. (A) Ribbon model of resistin trimer showing a C-terminal globular domain containing antiparallel β-sheets and an N-terminal α-helical domain. The three chains are indicated in cyan, yellow and lavender respectively. (B) Space-filled model of human resistin trimer. The basic (positively charged) amino acids, acidic (negatively charged) amino acids, and amino acid residues (Leu42, Pro46, Phe49, and Trp80) constituting the hydrophobic surface of the “head” region are shown in blue, red, and orange respectively. The structure was predicted based on the structure of mouse resistin structure (Protein Data Bank ID code 1RFX) and constructed by using the SWISS-MODEL program (https://swissmodel.expasy.org).

Figure 2

Function of resistin and the other RELMs in skin and intestinal epithelium. Human resistin and mouse RELMα are expressed in keratinocytes and sebaceous glands of skin that can be triggered by bacterial colonization and Vitamin A. Mouse and human RELMβ are expressed by goblet cells and epithelial cells into gastrointestinal tract mucus layer. They kill bacteria by binding to bacterial lipids and forming multimeric pores in bacterial membranes. All RELMs not only ① protect against pathogen colonization, but also ② limit access of the microbiota to host tissues and ③ determine microbiota composition.

Figure 3

Resistin signaling pathways in inflammation and immune regulation. Resistin binding to the TLR4, CAP1 receptors, GPCR, and unknown receptors activates several signaling pathways leading to the immune cell activation and migration, neutrophil dysfunction, pro-inflammatory cytokines and chemokines production, and NETs formation. The anti-LPS-induced inflammation mediated by resistin through TLR4 may be in two ways: ① Resistin competes with LPS/MD2 for binding to TLR4 and suppresses pro-inflammatory signaling (i. e., NF-κB) while promotes anti-inflammatory signaling (i.e., STAT3, TBK1); ② Resistin directly binds to LPS and neutralize its inflammatory (endotoxin) activity.

Figure 4

Immunomodulatory function of resistin. Resistin is involved in the host anti-infection immune process by interacting with a variety of immune cell types in humans. It can directly or indirectly promote the adhesion, infiltration, and migration of human monocytes, neutrophils, and CD4⁺ T cells. Likewise, resistin can activate monocytes, macrophages, and neutrophils, promote pro-inflammatory cytokines production, and reinforce IFNL3 expression. Moreover, it can also enhance extracellular bacterial killing, namely promote the formation of NETs. However, in certain diseases or contexts, resistin impedes human neutrophils’ function by inhibiting neutrophils migration and ROS production. It also inhibits antigen uptake, endocytosis, and cytokine production of human DCs, induces expansion of Tregs, and suppresses the proliferation and differentiation of CD4⁺ T cells into Th1 cells by regulating DCs.

Figure 5

Role of resistin in host defense. Leukocytes (i.e., macrophage, monocyte, and neutrophil) and skin epithelial cells-derived resistin act as host defense peptide, and participate in the innate anti-infection immunity of the host at least three ways: they directly kill bacteria; they regulate and balance the inflammatory response to microbial products (LPS and LTA); and they activate and amplify the host immune response to indirectly resist microbial infection.