The Contribution of Antimicrobial Peptides to Immune Cell Function: A Review of Recent Advances

Abstract

The development of novel antimicrobial agents to replace antibiotics has become urgent due to the emergence of multidrug-resistant microorganisms. Antimicrobial peptides (AMPs), widely distributed in all kingdoms of life, present strong antimicrobial activity against a variety of bacteria, fungi, parasites, and viruses. The potential of AMPs as new alternatives to antibiotics has gradually attracted considerable interest. In addition, AMPs exhibit strong anticancer potential as well as anti-inflammatory and immunomodulatory activity. Many studies have provided evidence that AMPs can recruit and activate immune cells, controlling inflammation. This review highlights the scientific literature focusing on evidence for the anti-inflammatory mechanisms of different AMPs in immune cells, including macrophages, monocytes, lymphocytes, mast cells, dendritic cells, neutrophils, and eosinophils. A variety of immunomodulatory characteristics, including the abilities to activate and differentiate immune cells, change the content and expression of inflammatory mediators, and regulate specific cellular functions and inflammation-related signaling pathways, are summarized and discussed in detail. This comprehensive review contributes to a better understanding of the role of AMPs in the regulation of the immune system and provides a reference for the use of AMPs as novel anti-inflammatory drugs for the treatment of various inflammatory diseases.

Keywords: anti-inflammatory; antimicrobial peptides; immune cell; immunomodulatory; inflammatory mediators; signaling pathways.

Figure 1

The regulatory mechanism of AMPs on macrophages (Drew in Figdraw.). AMPs inhibit apoptosis of macrophages, and enhance proliferation and phagocytosis of macrophages. AMPs inhibit LPS-induced inflammatory responses through P2X7R receptors or TLR2/4 receptors. AMPs inhibit Akt-p38 phosphorylation and NF-κB activation in different pathways induced by LPS through different receptors. Moreover, AMPs enter macrophages directly to block IKK phosphorylation, inhibit NF-κB pathway activation and production of the inflammatory factors.

Figure 2

The regulatory mechanism of AMPs on monocytes (Drew in Figdraw.). AMPs act on the TLR1/2 receptor and R2X7R receptor on the surface of monocytes, causing expression of CD80 and CD40 and activation of monocytes. AMPs inhibit production of the inflammatory mediators in monocytes after treatment with bacteria.

Figure 3

The regulatory mechanism of AMPs on lymphocytes (Drew in Figdraw.). AMPs induce apoptosis of CTLs and Tregs by inducing the release of granzyme. AMPs promote proliferation of T and B cells through NF-κB activation, and also directly enhance proliferation and activation of lymphocytes, and production of IL-12, IL-2, and IFN-γ by promoting transformation of Th cells into Th1 cells. T cells were stimulated by AMPs to produce IL-2/10 by inducing STAT1 serine phosphorylation and ERK1/2 threonine phosphorylation.

Figure 4

The regulatory mechanism of AMPs on mast cells (Drew in Figdraw.). AMPs induce an increase in Ca2+ concentration in mast cells through ERK and MAPK-p38 phosphorylation. By acting on the Mrgx2 receptor, mast cells release inflammatory mediators and cause degranulation, thus increasing vascular permeability, and recruit immune cells. AMPs directly inhibit production of ROS and TNF-α in mast cells induced by LPS.

Figure 5

The regulatory mechanism of AMPs on dendritic cells (Drew in Figdraw.). AMPs promote cytokine production by acting on TLR2 rather than TLR4 receptor on the surface of DC cells, and enhance production of INF-I by acting on the TLR9 receptor on the surface of MDC cells and then transform into a pro-inflammatory phenotype of DC cells. AMPs convert MDCs into DCs via TLR9, and produce TNF-α and IL-6.

Figure 6

The regulatory mechanism of AMPs on neutrophils (Drew in Figdraw.). AMPs promote production of apoptotic proteins Mcl-1 and Bcl-x, inhibit production of pro-apoptotic proteins BID and tBid, caspase-3 activation and neutrophil apoptosis, and enhance bactericidal ability through P2X7R, FPRL1, CCR6, and P2Y6 receptors. AMPs directly inhibit release of TNF-α and IL-6 in neutrophils induced by LPS. AMPs activate neutrophils to release NETs and inhibit release of inflammatory mediators by activating ERK and MAPK pathways.

Figure 7

The regulatory mechanism of AMPs on eosinophils. (Drew in Figdraw.). AMPs induce ERK phosphorylation through FPR2 receptors, enhance cPLA2 activity, and promote release of ECP, IL-6, and CXCL4/8 from eosinophils.