The inflammation response requires the cooperation of macrophages with immune cell function and active factors, such as cytokines and chemokines. Through this response, these factors are involved in the immune response to affect physiological activities. Macrophages can be categorized into two types: ‘M1’ and ‘M2’. M1 macrophages destroy the pathogen through phagocytosis activation, ROS production, and antigen-presenting, among other functions. M2 macrophages release cellular factors for tissue recovery, growth, and angiogenesis. Studies have determined that tumour tissue presents with numerous macrophages, termed tumour-associated macrophages. Tumour cells and peripheral stromal cells stimulate the tumour associated with macrophages (M2) to produce factors that regulate angiogenesis. Modulating the balance of the M1 and M2 function has already gained interest as a potentially valuable immune disease therapy. However, applications of the immunotherapy in clinical treatments are still not clear with regard to the cellular working mechanism. Therefore, we summarized the functions of common biomaterials involved in the modulation of the macrophage.
- tumour micro-environment
Inflammation has been demonstrated to be a critical factor in the induction of immune disease. Immunotherapy is a novel therapeutic approach for anti-inflammation, which could help avoid drug resistance. However, findings have indicated that the balance of inflammation and anti-inflammation is crucial. Cellular ROS are produced by stress to clear pathogen infections . The inflammatory response involves macrophages, dendritic cells, and M cells, which are crucial protectors. These cells present partial antigens to enhance the T-cell activation and cytokine production, which modulate the host micro-environment. Cytokines are produced and released as signals to regulate the immune cell function.
Immunotherapy was developed as an approach to rectify the imbalanced inflammation. Immunotherapy was hypothesized as a possible alternative therapy applied in the early phase of clinical therapy and immunomodulation in the early stages of immune disease. The common immunotherapy employs natural functional materials including triterpenoids and polysaccharides. Studies have demonstrated that functional polysaccharides can promote macrophage differentiation into M1 or M2, and the ratio modulates the host micro-environment through cytokine secretion.
Polysaccharides such as beta-glucan are considered to be biological response modifiers (BRMs) that activate macrophages and modulate the inflammation response. Findings have indicated that beta-glucan combines with receptors expressed on the macrophage cell surface, such as Toll-like receptor. Once combined, alveolar macrophages, Kupffer cells, Langerhans cells, mesangial cells, and microglial are activated through toll-like receptor 4–mediated signalling pathways to modulate the immune response.
2. Macrophage activation
Macrophages are present in almost all tissues and coordinate developmental, metabolic, and immunological functions, thereby contributing to the maintenance of homeostasis. Macrophages have a complex role in tissues and act on lipopolysaccharide (LPS), interferon-γ (IFN-γ), and interleukin (IL)-4 to polarize the M0 into M1. Macrophages are activated by exposure to various stimuli. The stimuli that act on macrophages are categorized into danger, homeostatic, metabolic, and modulatory signals. Danger signals include pathogen-associated molecular patterns, such as LPS. Tissue macrophage exposure to danger signals results in an inflammatory response. Findings have indicated that tumour environments contain numerous transmitters, such as M-CSF, IL-6, IL-10, TGF-β, and COX-2, which induce tumour megakaryocytes to differentiate into M2 macrophages, which, in addition to having poorer antigen-presenting and cytotoxic abilities, also secrete factors that inhibit immune cells, resulting in an enhanced immune inhibitory effect of the tumour environment as shown in Figure 1. We investigated the modulation of M1 and M2 in the tumour environment by using immunomodulators to delay or inhibit the tumour to identify alternative approaches to reduce the side effect of tumour chemotherapy. Inflammation is a crucial adaptive response for animals, and the mechanism involves a complex interaction of molecular mediators. The functions of immune cells in a micro-environment are mediated by responses that occur at all levels of biological organization . This process involves cooperation among cells and mediators, and the classical immune response varies based on a wide range of factors, including the stage of the inflammation process, the tissue or organ involved, and whether the inflammation is acute and resolving or chronic and nonresolving . The inflammation process involves vascular permeabilization, active migration of blood cells, and passage of plasma constituents into injurious tissue . Studies have demonstrated that the infiltration of immune cells during the inflammation process plays a crucial role in atherosclerosis . Blood leukocytes are mediators of host defences and inflammation localized in the earliest lesions of atherosclerosis in experimental animals. The study of inflammation in atherosclerosis provided new insights into the mechanisms underlying the recruitment of leukocytes . Recently, studies have indicated that inflammation plays a role in Alzheimer disease (AD) . Inflammatory components involved in AD neuroinflammation include brain cells (such as microglia and astrocytes), the complement system, and cytokines and chemokines . Regarding cancer development , proinflammatory cytokines, including chemokines; matrix metallopeptidase (MMP)-9; vascular endothelial growth factor (VEGF); and IL-1α, IL-1β, IL-6, IL-8, and IL-18, are primarily regulated by the transcription factor nuclear factor (NF)-kB, which is active in most tumours and is induced by carcinogens . Cutaneous wound repair is a tightly regulated and dynamic process involving blood clotting, inflammation, new tissue formation, and tissue remodeling . Thrombin is the protease involved in blood coagulation. Thrombin deregulation can lead to haemostatic abnormalities, which range from subtle subclinical to life-threatening coagulopathies (i.e., during septicaemia) . Inflammation and blood coagulation is part of the innate host protection mechanism against vascular injury, infection, or other wounds. Cells of the innate immune system, endothelial cells, and platelets are actively involved in acute and chronic inflammation; they release proinflammatory mediators and recruit leukocytes . The protease-activated receptor (PAR) family serves as sensor of serine proteinases in the blood clotting system in the target cells involved in inflammation. Activation of PAR-1 by thrombin and of PAR-2 by factor leads to a rapid expression and exposure of both adhesive proteins that mediate an acute inflammatory reaction and of the tissue factor that initiates the blood coagulation cascade on the membrane of endothelial cells . In this process, cooperation among cells and mediators occurs, and a wide range of factors are involved in the classical immune response: (1) the stage of the inflammation process; (2) the tissue or organ involved; and (3) whether the inflammation is acute and resolving or chronic and nonresolving . The inflammation process involves vascular permeability, active migration of blood cells, and the passage of plasma constituents into injurious tissue . Studies on the infiltration of immune cells have demonstrated that the inflammation process plays a crucial role in atherosclerosiss . Blood leukocytes, mediators of host defences and inflammation, localize in the earliest lesions of atherosclerosis in experimental animals. The study of inflammation in atherosclerosis has provided numerous new insights into the mechanisms underlying the recruitment of leukocytes . Studies have reported that inflammation is involved in Alzheimer’s disease (AD) . Inflammatory components involved in AD neuroinflammation include brain cells (such as microglia and astrocytes), the complement system, and cytokines and chemokines . Regarding cancer development, proinflammatory cytokines, including chemokines, MMP-9, VEGF, and IL-1α, IL-1β, IL-6, IL-8, and IL-18, are primarily regulated by the transcription factor NF-kB, which is active in most tumours and is induced by carcinogens [9, 10]. Macrophages play a crucial role in inflammation process, tumour growth, and tumour progression by induced angiogenesis. Studies have reported that promotion of angiogenesis with the production of proangiogenic factors, such as TGFβ, VEGF, PDGF, members of the fibroblast growth factors family, and angiogenic chemokines , and the development of breast cancer and several other human tumours was correlated with macrophage infiltration . VEGF-C production by tumour-associated macrophages (TAMs) was reportedly involved in peritumoral lymphangiogenesis and the subsequent dissemination of cancer cells with formation of lymphatic metastasis ; moreover, macrophage colony-stimulating factor (M-CSF) and VEGF actively recruit circulating blood monocytes at the tumour site .
3. Polysaccharide function on the immunomodulation
Evidence has indicated that acetyl-xylogalactan extracted from
Antimicrobial peptides are effective components of innate immunity that are widely present in the biological system. Hepcidin is a 25-amino acid antibiotic peptide synthesized in the liver, which is reportedly responsible for regulating iron balance and recycling in humans and mice. Studies on 0–100 μg/mL concentrations of hepcidin incubated with HT1080, Hep-G2, and HeLa for 24 h revealed higher growth inhibition ratios after treatment with 70 μg/mL hepcidin in HT1080 cells. Hepcidin was very effective at inhibiting the growth of fibrosarcoma cells [51, 52]. Studies on tachyplesin, an antimicrobial peptide present in leukocytes of the horseshoe crab (
Immunotherapy is being developed and presents certain advantages of alternative medicine because immunomodulation factors, such as mushroom beta-glucan, antimicrobial peptides, and triterpenoid, represent a novel therapeutic approach for cancer therapy and may provide an alternative to deal with the problem of drug resistance. However, exploring current insights into tumour biology and tumour micro-environment is complex and involves chemistry, biology, instrumentation, and formulation science. Therefore discovering a novel, more effective tumour-targeting treatment is difficult. Immunotherapy is hypothesized to be an alternative therapy that could be applied in the early phase of clinical tumour therapy.
The authors declare no competing interests.