ECOTIDE-Function of AMPs (Defensin) and it's Mechanism of Action
There are two main functions of AMPS in animal body. One is killing bacteria, another is increasing the immunity.
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1. Defensin, which belongs to the host defense peptide, is a defensive molecule for early defense response of mammalian mucosal immunity, and is an important component of the innate immune system, mainly distributed in the mucosa, immune organs and other parts. Defensins are defense methods that appear earlier than immune mechanisms such as lymphocytes and immunoglobulins. They are effective defense mechanisms retained by vertebrates during the long-term evolution of organisms.
2. The mucosal system is the first defense line of organism. In this line, defensins provide defense to the host through secretion or coupling with immune cells, so the organism is protected by “bathed” in body fluids composed of defensins and other antimicrobial proteins.
In the intestinal environment, defensins directly kill pathogenic microorganisms by destroying bacterial cell membranes, combine with endotoxins produced by bacteria, recruit immune cells etc., to enhance intestinal mucosal immunity, and promote the secretion of animal's own antibacterial proteins. However, in the intestinal environment of animal, the use of antibiotics, decline of micro-ecological diversity, increase in the number of harmful microorganisms, insufficient secretion of defensins, and inadequate development of intestinal mucosal immunity have become important reason for the decline of the resistance of young animal. Which provides a theoretical basis for us to add defensin and other endogenous biologically active substances to the feed.
3. The mucosal system has been in long-term contact with the outside world, and its cavity has formed a complex micro-ecological environment. In this environment, on the one hand, the intestine uses a crypt structure to distinguish the antigen-sensitive area from the non-sensitive area. On the other hand, after long-term animal evolution and domestication, resident microorganisms often get along with the host in a way of low-toxic lipopolysaccharide, non-adherent, and easy to be captured. Under normal circumstances, defensins are the main means of maintaining low concentrations of resident microorganisms. If there are resident microorganisms entering randomly, defensins will clear it. In the infected state, due to the characteristics of the resident microorganisms mentioned above----Low toxic lipopolysaccharide (which has relatively less negative charge), when the concentration of intestinal bacteria increases, the defensin will preferentially adsorb harmful microorganisms (lipopolysaccharide with high negative charge) and kill it, and eventually the whole intestine bacterial cell concentration is reduced to normal levels.
4. Although there are various models of antibacterial mechanisms such as the mode of action of antimicrobial peptide and the cell membrane, the structure of the complex, and the binding process, the peptide-lipid action form of the antimicrobial peptide is well-recognized, and the cell death caused by this combination is also beyond doubt.
5. Since most defensins are positively charged peptides, it can be combined with cell components such as unique negatively charged lipopolysaccharide or cell membrane phospholipids to destroy cell membrane structure and kill bacteria
6. Yount et al. studied the bactericidal process of antimicrobial peptides. Within 5 minutes after antimicrobial peptides invaded the bacterial cells, the bacterial cell membranes would completely lose their biological functions. In the next 60 minutes, the antimicrobial peptide will continue to penetrate into the inside of the cell and destroy the organelles. Within 60-120 minutes, the cell will enter a programmed death or autolysis state, and eventually disintegrate.
7. Defensins have bactericidal ability, but the immune regulation mechanism has a more important position in its function. Defensins are multifaceted in inducing mucosal immune responses. On the one hand, defensins can recruit immune cells and regulate mucosal immune responses. On the other hand, they can inhibit excessive inflammation and reduce the impact of chronic inflammation on animal growth.
In the intestine, when harmful microorganisms invade, pathogens or lipopolysaccharides and other sensitive substances will trigger an acute inflammatory response. In addition to killing invading microorganisms, defensins will recruit phagocytic cells to engulf bacteria, stimulate mast cells to release histamine, and dilate blood vessels to release more polymorphonuclear leukocytes and induce immune cells to produce more antibacterial proteins. If the bacteria are not completely eliminated, defensins will participate in the down-regulation of inflammatory signaling levels, inhibit the overexpression of stimulatory pro-inflammatory cytokines such as TNF-α and IL-6, and at the same time induce damage repair, angiogenesis, and stimulate T cells to produce specific immunity etc..
9. Studies have shown that defensins with β-sheet structure can induce cellular responses through G protein-coupled receptors mediated signaling pathways. For example, defensins can bind to CCR-6 on immune cells such as dendritic cells, macrophages, granulocytes, memory T cells, and lymphocytes to achieve cell signal transduction. α、β defensins induce immune cells to release histamine and prostaglandin D2 by relying on G protein-phosphatase C signaling pathway. Defensin can activate the complement pathway and increase the release of TNF-α and IL-1β, while defensin-2 can also activate immature dendritic cells through the TLR-4 receptor.
In these processes, defensins mainly act as signaling molecules, so defensins are very important in the process of mucosal immune response
10. In terms of reducing inflammation, defensins can reduce the damage of inflammation to the organism by reducing excessive inflammation and reducing the occurrence of sepsis symptoms. After antibiotics kill the microorganisms, they cannot remove a large amount of residual bacterial lipopolysaccharides, which will lead to various inflammatory reactions and sepsis symptoms caused by lipopolysaccharides at a later stage. Compared with antibiotics, defensins inhibit lipopolysaccharide binding to TLR on the surface of immune cells by binding lipopolysaccharide, thereby inhibiting the nuclear localization signaling pathway mediated by TLR, and by inhibiting the over-expression of pro-inflammatory factors TNF-α, IL-6, etc., reduce excessive inflammation or sepsis symptoms, and ultimately reduce the diarrhea caused by lipopolysaccharide.
11. The mechanism of defensins in the intestine is global. With the help of a special intestinal structure--crypt, the concentration of defensins in the intestine is distributed in a gradient from the crypt to the intestinal cavity. Among the crypts where most in need of protection, the highest concentration of defensins plays a role in killing microorganisms and protecting intestinal stem cells; In the mucus near the intestinal epithelial cells, the defensin concentration is moderate, which plays a role in controlling the resident microorganisms; at the far end, the defensin concentration is low, which can be used as an immune signaling factor to regulate mucosal immunity. Therefore, adding appropriate defensins to animal feed has a good effect on improving intestinal mucosal immunity and maintaining intestinal microecological balance.
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