26 January 2025
College of Medical Imaging and Laboratory, Jining Medical University, Jining 272067, China
College of Medical Engineering, Jining Medical University, Jining 272067, China
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
The interaction between the neuroendocrine system and the immune system plays a key role in the onset and progression of various diseases. Neuropeptides, recognized as common biochemical mediators of communication between these systems, are receiving increasing attention because of their potential therapeutic applications in immune-related disorders. Additionally, many neuropeptides share significant similarities with antimicrobial peptides (AMPs), and evidence shows that these antimicrobial neuropeptides are directly involved in innate immunity. This review examines 10 antimicrobial neuropeptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), α-melanocyte stimulating hormone (α-MSH), ghrelin, adrenomedullin (AM), neuropeptide Y (NPY), urocortin II (UCN II), calcitonin gene-related peptide (CGRP), substance P (SP), and catestatin (CST). Their expression characteristics and the immunomodulatory mechanisms mediated by their specific receptors are summarized, along with potential drugs targeting these receptors. Future studies should focus on further investigating antimicrobial neuropeptides and advancing the development of related drugs in preclinical and/or clinical studies to improve the treatment of immune-related diseases.
Recent studies have revealed the elaborate crosstalk between the immune and nervous systems [1]. These systems use a shared biochemical language, including neurotransmitters such as neuropeptides and hormones, immune ligands, and their receptors [2]. This interaction forms a bidirectional communication network. Neuropeptides are key players in this process, regulating specific neuroimmune disorders [3].
Antimicrobial peptides (AMPs) serve as the primary line of defense for the host against pathogenic organisms and possess the capacity to elicit innate immune responses [4]. Some neuropeptides produced by neurons, glial cells, and immune cells exhibit physical properties comparable to those of AMPs and have been verified to possess specific antimicrobial properties [5]. Moreover, neuropeptides function as neuroendocrine modulators [6], playing a vital role in the modulation of inflammatory responses [7]. The receptors for these neuropeptides serve as essential targets for immune regulation [7]. Potential therapeutic agents targeting their respective receptors are anticipated to be viable treatments for specific immune disorders and to progress toward clinical therapy [8,9,10].
Neuropeptides that exhibit antimicrobial and immunoregulatory properties have the potential to significantly impact the pathophysiology of various immune-related diseases [11]. This review provides a comprehensive examination of the immune regulatory mechanisms mediated by neuropeptides, along with an analysis of their sources, target cells, and immunoregulatory functions of antimicrobial neuropeptides. Furthermore, we summarize the receptors for the 10 most prominent antimicrobial neuropeptides, including their respective agonists and antagonists, as well as the implications for disease treatment. By leveraging the immune-regulating properties of those antimicrobial neuropeptides, we propose that they may play a substantial therapeutic role in specific diseases.
Traditionally, the neuroendocrine system and the immune system have been viewed as distinct regulatory domains that govern homeostasis between the host and its environment [12]. Each domain is characterized by its own specialized terminology, and only a limited number of researchers possess expertise in both areas [13]. It was not until the late 1970s, with advancements in research into both the immune and neuroendocrine systems, that the complex crosstalk between these two systems was elucidated [12,14]. The neuroendocrine system and the immune system communicate internally through a biological regulatory signal library. Immune cells can respond to stimuli by secreting neurotransmitters, whereas the neuroendocrine system can modulate immune responses through the production of cytokines [13,15,16] (Figure 1). This interplay between the neuroendocrine system and the immune system is essential for pathogen elimination and the re-establishment of immune homeostasis [17]. Neuropeptides, a class of neuroendocrine mediators, are secreted by both immune and nerve cells. The literature has established that neuropeptides act as multifunctional regulators of the immune response [6] and are capable of activating immune cells to elicit either anti-inflammatory or pro-inflammatory effects.
The induction of immune tolerance is vital for maintaining immune homeostasis, modulating autoreactive T cells, preventing the onset of autoimmune diseases, and achieving transplant tolerance [7]. Inflammation is a crucial physiological response against pathogen eradication; however, the inadequate regulation of this process can lead to significant adverse effects on the host [7]. Investigating the endogenous factors that influence immune tolerance and inflammation represents a significant research focus within the field of immunology. Between 2000 and 2008, Delgado’s research team reported that neuropeptides synthesized by nerve cells and immune cells have anti-inflammatory properties and facilitate the maintenance of immune homeostasis. These neuropeptides include vasoactive intestinal peptide (VIP), α-melanocyte-stimulating hormone (α-MSH), urocortin I (UCN I), adrenomedullin (AM), and cortistatins [7,12,17].
A previous study revealed that CD4+ and CD8+ TH2 immune cells are the primary sources of VIP in response to inflammatory stimuli or antigen activation [7]. Additionally, α-MSH is predominantly expressed in lymphocytes and monocytes, and its production is stimulated by inflammatory factors [19]. Research has shown that VIP and α-MSH act as potent anti-inflammatory agents, effectively inhibiting the production of inflammatory mediators (TNFα, IL-6, and IL-1β) and chemokines (CCL5, IL-8, and IP-10), downregulating inducible nitric oxide synthase (iNOS) expression, and thus diminishing nitric oxide (NO) release. Meanwhile, the activation of macrophages, microglia, and monocytes enhances the production of the anti-inflammatory cytokines IL-10 and TGFβ [7]. Concurrently, VIP and α-MSH play crucial roles in modulating the balance between TH1 cells and regulatory T cells within the organism (Figure 2). This regulation ensures a stable equilibrium between anti-inflammatory and pro-inflammatory factors, thereby reducing the risk of autoimmune diseases [7]. Moreover, neuropeptides can influence macrophages to effectively modulate the M1/M2 balance and enhance the body’s anti-inflammatory capacity (Figure 2) [20].
Additionally, UCN I, AM, and cortistatin, which are synthesized by nerve and immune cells (such as macrophages, monocytes, lymphocytes, or T cells), act as endogenous immunoregulatory factors with substantial anti-inflammatory properties [7]. They are capable of inhibiting the production of pro-inflammatory cytokines (TNFα, IL-6, IL-12, IL-1β, and MIF), chemokines (CCL5, IP-10, MIP-1α, MIP-2, MCP-1, and eotaxin), and NO, whereas they stimulate immune cells to produce the anti-inflammatory cytokine IL-10 [7].
The inflammatory response is a highly complex process involving numerous factors and signaling pathways. As a crucial component of the body’s defense and protective mechanisms, the inflammatory response is essential for eliminating harmful foreign substances and initiating self-repair processes [21]. Generally, regulated pro-inflammatory responses are not harmful; rather, they are crucial for maintaining homeostasis under normal conditions [22]. During the onset of an inflammatory response, certain neuropeptides act as immunomodulators by interacting with various receptors to facilitate the progression of inflammation [23]. Certain neuropeptides synthesized by neuronal and immune cells play a significant role in modulating pro-inflammatory responses; the primary neuropeptides involved include substance P (SP), calcitonin gene-related peptide (CGRP), and neuromedin U (NmU) [24,25].
Neuropeptides primarily trigger pro-inflammatory responses by stimulating or enhancing the expression of pro-inflammatory cytokines [26]. For example, SP and CGRP can promote the release of pro-inflammatory cytokines (TNFα, IL-1, and IL-4) and histamine from mast cells, thereby fostering an environment conducive to inflammation (Figure 3) [27,28,29,30]. Furthermore, neuropeptides can induce inflammation by regulating the balance between anti-inflammatory and pro-inflammatory factors. For example, SP downregulates the mTOR signaling pathway, reduces the expression of the anti-inflammatory cytokine IL-10, and enhances the release of the pro-inflammatory cytokines IL-12p40 and IL-23, which subsequently increases susceptibility and promotes inflammatory responses [31]. Recent research has indicated that NmU can be upregulated in response to pathogen infection, promoting type 2 cell responses and activating eosinophils, thus inducing pro-inflammatory effects [25].
Neuropeptides function as neuroendocrine regulators [6], with certain neuropeptides displaying antimicrobial properties that play crucial roles in immune regulation [7,23]. The neuropeptides under consideration include pituitary adenylate cyclase-activating polypeptide (PACAP), VIP, α-MSH, AM, neuropeptide Y (NPY), urocortin II (UCN II), CGRP, SP, and catestatin (CST). This study conducted a thorough analysis of the expression characteristics of these ten antimicrobial neuropeptides and their corresponding receptors (Table 1). Additionally, we performed a comprehensive systematic review of potential therapeutic agents targeting these receptors, along with an evaluation of their clinical viability in preclinical and/or clinical studies (Table 2).
PACAP is a neuropeptide consisting of 38 amino acids that was first isolated from the hypothalamus of sheep by Atsuro Miyata and colleagues in 1989 [109]. This neuropeptide is widely distributed throughout the nervous and immune systems, is predominantly found in thymic cells and lymphocytes, and is classified within the secretin/glucagon/VIP superfamily [32]. The receptors VPAC1, VPAC2, and PAC1 are utilized by both PACAP and VIP [110]. Although PACAP and VIP display similar affinities for VPAC1 and VPAC2 [111], the affinity of PACAP for PAC1 is approximately 300–1000 times greater tha
