Immunomodulatory Activity of Antimicrobial Peptides

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1		Svetlana V. Guryanova	+ 3739 word(s)	3739	2022-03-02 02:57:20	\|
2	format correct	Nora Tang	Meta information modification	3739	2022-03-18 03:09:48	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms23052499

Antimicrobial peptides (AMPs) in humans are represented by three main families: defensins, cathelicidins, histatins. Defensins, depending on the type of disulfide bond arrangement, are divided into alpha- and beta-defensins. Alpha- and beta-defensins are constitutively produced by neutrophils, lymphocytes, and epithelial cells of the skin and mucous membranes.

antimicrobial peptides defensins cathelicidins innate immune system

1. The Effect of AMP on Humoral Immunity

The effect of antimicrobial peptides (AMPs) on humoral immunity was assessed by their ability to stimulate the production of antibodies, cytokines, and complement activation.

1.1. Adjuvant Activity of AMPs

AMPs, as components of innate immunity, take part in triggering an antigen-specific immune response, promote intercellular cooperation and increase the production of antibodies. It was shown that intranasal administration of ovalbumin (OVA) together with defensins HNP1–3 to mice increased the production of specific IgG and IgM, but not IgA. The authors of the study concluded that defensins enhance the systemic immune response, but not the mucosal one ^[1].

Intraperitoneal administration of defensins HNP 1–3 to mice significantly increased the production of KLH-specific antibodies IgG1, IgG2a, and IgG2b after 14 days from immunization. Defensins also significantly increased the production of antibodies to the antigen of a syngeneic tumor and increased the resistance of animals to a transplantable tumor ^[2]. These results indicate that defensins act as potent immune adjuvants, enhancing the production of antigen-specific immunoglobulins.

The adjuvant activity of defensins is used in the development of vaccines against viral and bacterial infections. In particular, the mycobacterium Mycobacteroides, which is pathogenic to humans and frequently causes postoperative infectious complications, and is also found in patients with soft tissue infections, is very resistant to conventional antimicrobial drugs. The addition of hBD-2 as an adjuvant to the vaccine against Mycobacteroides has increased the effectiveness of therapy ^[3]. Defensin hBD-2 enhances the antigen-specific immune response not only against bacterial, but also toward viral antigens. The introduction of hBD-2 defensin into the vaccine increases the immunogenicity of vaccines against hepatitis B ^[4] and hepatitis C, both in free ^[5] and conjugated with a polypeptide form ^[6]. hBD-2 is being introduced as an adjuvant in MERS-CoV vaccines under development ^[7]^[8]^[9].

The adjuvant effect of human defensins, manifested against bacterial and viral infections, made it possible to formulate the concept of a “defensin vaccine” as a conceptual basis for constructing vaccines ^[10].

The effectiveness of the adjuvant impact of defensins increases by several times when administered together with hBD-2 or hBD-3 and with CpG nucleotides. Intraperitoneal immunization of mice with hBD2,3/CpG complexes increased the humoral response to OVA in comparison with only OVA/hBD3 or OVA/CPG by 5 and 10 times, respectively ^[11].

In the current epidemiological situation, researchers from different countries are using defensins to create vaccines against SARS-CoV-2. Approaches are being developed for conjugating defensins with T- and B-cell epitopes in vaccines against SARS-CoV-2. It has been shown that the binding of three structural polypeptides (spike, membrane and nucleocapsid (SMN)) with hBD-2 and hBD-3 at the N- and C-termini, respectively, increases the immunogenicity of the vaccine in the absence of an allergenic effect ^[12]^[13]^[14].

1.2. The Effect of AMPs on the Cytokine and Chemokine Production

Constitutively synthesized AMPs maintain a balance of immune homeostasis not only through direct action on the pathogen and its elimination, but also via activation of the production of cytokines and chemokines that attract immunocompetent cells to the pathogen invasion zone. Thus, a multilevel protection of the body against infection is realized.

In a comprehensive study of the effect of hBD-1, hBD-2, and hBD-3 on the production of cytokines by peripheral blood cells (PBMC), the selective activity of defensins was shown ^[15]. hBD-1 increased the production of IL-6, IL-8, IL-10, MCP-1 (Monocyte Chemoattractant Protein 1, CCL2), and EGF (Epidermal Growth Factor) on the first day. IGFBP-3 (Insulin-like Growth Factor-Binding Protein 3) increased on the first day and decreased after 6 days. hBD-1 significantly lowered IL-5 and had no effect on IL-1-β, IL-16, and MCP-2. hBD-2 dose-dependently stimulated the induction of cytokines IL-1-β, IL-6, IL-8, IL-10, ENA-78 (CXCL5), IGFBP-3 (Insulin-like growth factor-binding protein 3), EGF (Epidermal growth factor), and HGF (Hepatocyte growth factor). The maximum activity in relation to IL-6 and IL-10 production was observed after 8 h, and that of IL-8 was observed after 18 h. hBD-3 exhibited the least activity of the three defensins, increasing only IGFBP-3 and MCP-1 slightly, while decreasing the level of IL-10 and HGF (Hepatocyte Growth Factor). Interestingly, some cytokines such as IL-8 and MCP-1 were activated by all three defensins, while IL-16 was activated by none of the tested defensins. It is noteworthy that each defensin induced a unique set of cytokines. A multidirectional action of defensins with respect to IL-10 was found: hBD-1 and hBD-2 activated its synthesis, while hBD-2 inhibited it.

In experimental studies of the effect of hBD-1 on human bronchial epithelial cells, a dose-dependent increase in IL-8 and IL-1 was observed ^[16]. While investigating human keratinocytes, it was shown that at a concentration of 5 to 8 μg/mL, hBD-2, hBD-3, and hBD-4 but not hBD-1 had a stimulating effect, which led to an increase in the production of IL-6, IL-10, MCP-1, and MIP-3. In this case, the cytotoxic effect of defensins was manifested at a dose of 50 µg/mL ^[17]^[18].

hBD-2 and hBD-3, when co-administered with CPG, increased the IFN-α synthesis by human plasmacytoid dendritic cells and induced inflammation. Intravenous (I.v) administration of hBD3/CpG complexes to mice induced the production of proinflammatory cytokines such as IL-12, IFN-γ, IL-6, IFN-α, and IL-10 in blood serum ^[11].

Alpha defensins 1–3 also increased the ex vivo production of IFN-γ in KLH-activated spleen cell supernatants from mice ^[2].

Intranasal immunization of mice with ovalbumin (OVA) with the subsequent administration of human alpha defensins 1–3 increased the production of IFN-γ, IL-5, IL-6, and IL-10 compared to control groups immunized with ovalbumin ^[1].

When studying the effect of alpha-defensins HNP1–3 on human lung epithelial A249 cells with regards to the production of pro-inflammatory and anti-inflammatory cytokines IL-1 β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, IFN-γ and GM-CSF, a dose-dependent ability of HNP1–3 to induce IL-8 production was found. It is important to note that the HNP-induced IL-8 release was observed even at very low doses (3 μg/mL) of alpha-defensins ^[19].

Human AMP cathelicidin LL-37 induces the production of cytokines IL-6, IL-8 and IL-10, as well as of CC-chemokine ligand 2 (CCL2) ^[20] and can act synergistically with IL-1β to increase the production of cytokines IL-6, IL- 8 and IL-10, as well as the chemokine CCL2. Cathelicidin LL-37 also increases the synthesis and release of alfa-defensins, forming a positive feedback loop that enhances the inflammatory process ^[21]. Similarly, hBD-1 and HNP-1, acting on dendritic cells, also enhance their own expression ^[22].

In some cases, the induction of pro-inflammatory cytokines may be undesirable, and therefore synthetic AMPs with antibacterial properties and anti-inflammatory activity were created. Based on the analysis of the AMP structures, modified tryptophan-containing amphipathic helical undecapeptides (WALK11), exhibiting antimicrobial activity with significant anti-inflammatory potential, were synthesized ^[23]. With the use of cells of the mouse macrophage line RAW264.7, the WALK11 peptide was shown to inhibit the expression of inflammatory mediators IL-1β, IL-6, INF-β, and TNF-α, while maintaining antibacterial activity.

1.3. AMPs’ Action on the Complement System

Alpha-defensin HNP-1 inhibits the classical and lectin pathways of activation of the complement system at an early stage, forming C1q and MBL complexes, thereby protecting the body from tissue damage ^[24].

Invertebrate AMPs can also affect the human complement system, and, depending on the concentration, the effect is multidirectional. In particular, the peptide arenicin-1 from the marine polychaete Arenicola marina at relatively low concentrations (1–40 µg/mL) stimulates complement activation and lysis of target erythrocytes, while at higher concentrations (80–160 µg/mL), arenicin acts as a complement inhibitor. The authors of this study discuss the possibility of interaction of AMPs with complement proteins, C1q and C3, and the regulation of their functional activity ^[25]. The influence of structural changes in arenicins on their interaction with complement proteins and biological activity was studied ^[26]. The arenicin-1 derivative without a disulfide bond (Ar-1- (C/A)), despite the absence of this bond, retains all important functional activities and also exhibits lower toxicity compared to the natural analogs previously discovered ^[27]^[28]^[29].

In another study, the AMP tachyplesin-1 from the horseshoe crab Tachypleus trindentatus complexed with the human C1q complement protein and triggered the classic complement pathway. The authors used this property of tachyplesin-1 to study the possibility of tachyplesin-1 to bind to the surface of human prostate carcinoma TSU cells, and to attract proteins of the complement system to destroy carcinoma. It was found that the cytotoxic effect of tachyplesin-1 and C1q on human prostate carcinoma cells TSU is realized only if the spatial structure of the peptide is preserved, since the reduction and alkylation of disulfide bonds of tachyplesin-1 led to weak binding to C1q and less cytotoxic effect ^[30].

Obviously, AMPs can be considered as promising compounds for creating new therapeutic agents that regulate the work of the complement system, both with the aim of destroying infected and transformed cells, and with the aim of preventing complement activation.

2. The Effect of AMPs on Immunocompetent Cells. Chemotactic Activity of AMPs

Along with direct inactivation of bacteria, fungi and viruses, AMPs exhibit different effects on the cells of a host organism. Interaction of AMPs with immunocompetent cells of the human and animal body with their further activation so as to form an adequate immune response to the pathogen is an important property of AMPs. Recently, it has become obvious that the main function of AMPs is not only to directly destroy the pathogen at the initial stage, but also to attract phagocytic and cytotoxic cells for the elimination of killed bacteria at a later stage, trigger inflammatory reactions in the case of ineffectiveness of the initial stage and induce anti-inflammatory reactions for relief, completion of the process of inflammation and restoration of damaged epithelium.

The attraction of immunocompetent cells to the inflammation zone is carried out through the expression of chemokines and their receptors. The AMP triggering of the proinflammatory immune response is carried out with the participation of both the humoral factors described above and the cooperative interaction of immunocompetent cells.

AMPs possess a chemotactic activity for neutrophils, macrophages, and immature dendritic cells ^[31]^[32] and cause mast cell degranulation ^[33]^[34]. Defensins attract neutrophils to the area of inflammation, as well as cells that express the human chemokine receptor CCR6. It has been established that human alfa-defensins caused monocyte chemotaxis in vitro. HNP-1 demonstrated the most significant activity, HNP-2 was less active, while HNP-3 did not display a chemotactic effect ^[32]. These AMPs also caused chemotaxis of immature human dendritic cells and naive T-lymphocytes ^[35]. Beta-defensins hBD1–3 also induced chemotaxis of T cells and immature dendritic cells by binding to the chemokine receptor CCR6 or CCR2 ^[36]^[37]^[38]. Furthermore, beta-defensins stimulated the migration of keratinocytes ^[18] and endothelial cells of the human umbilical cord ^[39].

Beta-defensin-induced chemotaxis was sensitive to the pertussis toxin and was inhibited by antibodies to CCR6 ^[36]. CCR6 is predominantly expressed by immature monocytic dendritic cells (DC) and CD8 + T cells ^[33]^[35]^[40]. As a result of cooperative interaction, maturation of DCs from monocytes occurs. DCs activate CD4 + T cells and CD8 + T cells, as well as B cells. At this point, defensins induce the release of proinflammatory cytokines IFN- γ, IL-6, and IL-10 from monocytes ^[41]^[42]^[43]. However, it has also been shown that beta-defensins can recruit CD4 + T cells and dendritic cells through another CCR6-independent, not yet identified, receptor ^[44].

In addition, alpha defensins induce the expression on CD4+ T-lymphocytes of the co-stimulatory molecules CD28, CD152\CTLA 4 and CD11a\LFA1 ^[45]. Under the action of beta-defensins, monocytes and Th17 produce the cytokines IL-17, IL-22, and TNF- α, which can increase inflammation, limiting the spread of the infectious process ^[46].

Investigation of the mechanism of the effector action of hBD-3 on T cells demonstrated that hBD-3 induced tyrosine phosphorylation of STAT1 and suppressed tyrosine phosphorylation of STAT1 in the case of IFN-γ exposure. Signaling pathways initiated by hBD-3 can lead to an increase in various T cell effector functions during T cell receptor activation, such as an increase in IL-2 and IL-10 levels. hBD-3 simultaneously initiated the signaling cascade of tyrosine kinase and tyrosine phosphatase, which can simultaneously activate T cells and inhibit their response to other immune mediators ^[47]. The immunosuppressive role of hBD-3 has been confirmed in vitro on human peripheral blood monocytes and in vivo on mouse macrophages hBD-3 and the mouse orthologue Defb14 (but not hBD-2) effectively inhibited the production of LPS-induced serum TNF-alpha and IL-6 ^[48].

hBD-2 and hBD-3 can regulate their own production as well as the development and function of Treg and Teff cells. Analysis of the expression of the specific marker of regulatory T cells (Tregs) FoxP3 when incubating T cells with hBD-2 and hBD-3 showed an increase in CD4+CD127-CD25+ Treg after 18 h and a decrease in Treg after 42 h of incubation in vitro due to loss of the FoxP3 expression. hBD-2 and hBD-3 control polarization of human CD4+ T cells and their ability to induce differentiation of effector T cells into RORγt + Tbet + (Th17/Th1) cells and Treg cell differentiation. This plasticity of the T cell phenotype also allows them to convert from Tregs to an effector T cell phenotype like Th1/17 after 18 h of culture. By 42 h of culture, treatment with hBD-2 and hBD-3 induced the differentiation of both Teff and Treg cells towards a Th17-like phenotype. Compared to hBD-2, hBD-3 caused a more pronounced effect of increasing RORγt levels in CD4+ T cells. This increased expression may be responsible for the induction of an increased IL-17A secretion. It was also found that hBD-3, but not hBD-2, was able to induce a higher level of the IL-17A secretion. In addition, treatment with hBD-3 induced an increased expression of IL-6, which was capable of directing the differentiation of naive T cells towards IL-17-producing Th17 cells. These data indicate that hBD-2 can inhibit the ability of Treg cells and cause suppression of Teff cell activity. Interestingly, co-cultivation with hBD-2 also increases the resistance of Teff cells to Treg immunoregulation in vitro. The use of genetic analysis on microarrays identified the chemokine ligand CC-motif 1 (CCL1) as a potential gene responding to the effects of hBD-2. It turned out that CCL1 blockade inhibited the suppressive function of Treg. The effect of hBD-2 and hBD-3 on Treg and Teff demonstrates the plasticity of T-cell phenotypes and the indirect effect of defensins on adaptive immunity ^[49].

Opposite data were obtained when hBD-2 was exposed to human peripheral blood T cells, in which stimulation of IFN-γ and IL-10 and suppression of IL-17 production were observed. Perhaps, the plasticity of T-lymphocytes and their dependence of the microenvironment and the duration of exposure to beta-defensins can serve as a presumable explanation ^[50].

The human alpha-defensins are chemoattractants for macrophages, T-lymphocytes, and mast cells ^[51]. In the analysis of cross-regulation between human alfa- and beta-defensins, it was found that the alfa-defensin receptor was cross-desensitized by beta-defensins. In contrast, alfa-defensins desensitize beta-defensin-mediated migration of immune cells, which indicates joint receptors for both defensin families ^[51].

While alpha- and beta-defensins stimulate the proliferation of T cells, another AMP, human cathelicidin LL-37, showed chemotactic activity for neutrophils, monocytes, and CD4+ T-lymphocytes ^[52] and induced apoptosis in regulatory T cells ^[53].

AMPs can limit inflammation. For example, depending on the microenvironment, alfa-defensins can block the secretion of IL-1β by monocytes activated by lipopolysaccharide (LPS) ^[54].

The effect of defensins on human monocytes depends on the maturity of the immune system. When investigating the effect of hBD-1 on neonatal umbilical monocytes, hBD-1 was found to induce the production of GM-CSF and IL-4, but not inflammatory cytokines. In this case, hBD-1 promotes the differentiation of neonatal monocytes from umbilical cord blood into immature dendritic cells (DCs) and then the final maturation of DCs. In addition, hBD-1 inhibited apoptosis through CCR6 in dendritic cells derived from neonatal monocytes. In relation to neonatal CD4+ T cells, hBD-1 promoted proliferation and activation, but not their maturation ^[55].

hBD-2 and hBD-3 activate plasmacytoid dendritic cells (pDCs), increasing intracellular uptake of CpG. In this case, CpG and host DNA form aggregates with hBD-2 and hBD-3 ^[11]. The effect of defensins on B cells is indirect, and it is realized through the interaction of B and T cells. This increases the systemic response and the synthesis of IgG, but not IgA, due to the assistance provided by the cytokines Th1 and Th2 ^[1].

Manifestation of multivarious effects of AMPs depends on their concentration in blood. At pico- or nanomolar concentrations, they can bind to certain receptors on the cell surface and cause, for example, chemotaxis of immunocompetent cells. At micromolar concentrations, which are observed in an infectious process and inflammation, AMPs exhibit antimicrobial activity and can have a toxic effect on the cells of the host organism.

In particular, the concentration of defensins is critical for the realization of their activity. At 5 μM and higher, hBD-3 can cause damage to monocyte membranes (but not membranes of B and T cells) due to interaction with negatively charged phospholipids ^[56]. Similarly, the concentration of HNPs released into the microenvironment upon activation of neutrophils during inflammation exerts a differential effect on cytokine production in activated monocytes. HNP concentrations from 1 to 10 nM can upregulate the expression of tumor necrosis factor alfa (TNF-α) and interleukin-1β (IL-1β), whereas concentrations from 10 to 100 µM are cytotoxic to monocytes ^[54]. The revealed selectivity of the activity of various human defensins indicates the presence of a fine regulation mechanism of immune homeostasis by AMPs ^[15].

AMP cathelecidin LL-37 attracts monocytes, neutrophils, and T-lymphocytes to the inflammation focus, interacting with the surface receptor FPRL1 (formyl peptide receptor-like 1) presented on these cells ^[52].

The wide spectrum of defensin activity on immunocompetent cells, their selectivity and ability to shift the proinflammatory response to an antiinflammatory one have led to the assumption that the immunomodulatory activity of defensins is no less important than the antibacterial activity, and it serves as a key factor in the binding of the innate and adaptive immune response ^[2]^[57]^[58].

When comparing the cytotoxic and antibacterial properties of alpha- and beta-defensins, it was found that beta-defensins may be more suitable antimicrobial agents for clinical use than alpha-defensins due to a less pronounced cytotoxic effect ^[17], and the most active among beta-defensins, hBD-3, can be considered as a candidate AMP ^[59]^[60].

The properties of other immune cells can also be altered by the action of AMPs, which can initiate degranulation of mast cells, participating in the development of inflammatory and allergic reactions. Mast cells are highly specialized cells playing a key role in the development of inflammation. When mast cells are activated, a broad spectrum of different molecules are released and act as mediators of inflammatory reactions. Both human α- and β-defensins have been shown to cause degranulation of mast cells ^[61]^[62]^[63]. Human cathelicidin LL-37 also exhibits this type of activity ^[62]. LL-37 induces the release of histamine by mast cells, as well as the secretion of IL-1β, IL-4, and IL-5 ^[34]. Thus, AMPs from neutrophils and barrier epithelium can be involved in the development of inflammation, chemotaxis and degranulation of mast cells.

AMPs can not only affect immunomodulating cells, they are also mediators of endocrine–immune interactions and have corticostatic activity. It has been shown that beta-defensins are expressed in human and mouse pancreatic endocrine cells ^[64], weaken the autoimmune response, and reduce the subsequent development of diabetes by increasing the proliferation of pancreatic beta cells and the number of Treg cells. It has been proven that changes in the AMP repertoire in tuberculosis are associated with the severity of the disease, the clinical picture, specific therapy, and the level of immunoendocrine mediators. In newly diagnosed patients with pulmonary (PTB) or pleural tuberculosis (PLTB), it was found that severe PTB patients displayed higher circulating amounts of hBD-3, statistically different from control ones. At the same time, LL-37 concentrations appeared within the normal range. PLTB patients revealed decreased levels of hBD-2 and increased amounts of hBD-3 and LL-37 in pleural fluids and plasma. Considering the immune-endocrine dysregulation in tuberculosis, there were detected positive correlations between levels of cortisol, IL-6 and β-defensin-3 in plasma from untreated severe patients and their dehydroepiandrosterone and LL-37 values. The different profile of PLTB patients, decreased hBD-2 along with increased hBD-3 and LL-37 levels, suggests a differential role of these hDPs in a host defense ^[65]. The discovered correlation raises the question of causation, the answer to which might be provided by further studies aiming to prove that dehydroepiandrosterone promotes the production of hBD-2 and hBD-3 in infected cells, correlating with the decrease of Mycobacterium tuberculosis bacilli loads ^[66].

Alfa-defensin inhibited ACTH-induced corticosterone production by rat adrenal cortex cells in vitro ^[67]. This defensin also inhibited ACTH-induced aldosterone synthesis by rat adrenal cells, but had no effect on angiotensin II-stimulated aldosterone production ^[67], although it inhibited aldosterone synthesis induced by α-melanocyte-stimulating hormone ^[68]. It was found that the administration of the RatNP-3 defensin immediately before stress exposure reduced the stress-induced increase in blood corticosterone concentration and normalized stress-induced changes in the number of neutrophilic granulocytes in the blood of rats ^[69].

There was no correlation between human defensins (HNP-1 and hBD-1) and cortisol and testosterone levels in a study of defensins and hormones levels in athletes experiencing prolonged physical activity. Observations during 12 months showed a 29% increase in HNP-1 levels after 3 months, and a 10-fold increase in hBD-1 after 6 months, which persisted throughout the entire observation period. At the same time, cortisol and testosterone levels peaked at 6 months, and returned to their original levels after 12 months ^[70].

In addition, beta-defensins are expressed in different segments of the testis ^[71], and have a main function in sperm maturation. A beta-defensin mutation at the DEFB126 locus was found to decrease sperm motility and fertility in men ^[72]. Mice with deletion of two or more beta-defensin genes are infertile ^[73]. Alpha-defensin HNP-1 can restore the ability to proliferate Schwann cells, influencing the regeneration of peripheral nerve damage, inhibiting cell aging and apoptosis ^[74].

The effect of defensins on the intestinal mucosa is decisive for maintaining homeostasis. The absence of defensin expression contributes to an increase in the number of pathogenic bacteria and is observed in inflammatory bowel diseases ^[75]. At the same time, an increased amount of defensins may indicate the intensity of the immune response when the content of opportunistic pathogens is increased ^[76].

Currently, more and more data point to participation of AMPs in the interaction between the innate and acquired immunity systems. The effect of AMP on different types of immunocompetent cells may be direct or intermediated ^[77]. AMPs have an effect on the functional activity of dendritic cells, which, in turn, modulate the activity of lymphocytes. AMPs are also produced by the immunocompetent cells, which can secrete these molecules during the development of the immune response. As a result, special immunomodulatory activity of AMPs are realized ^[78].

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