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This review aimed to take stock of the current status of research on damage-associated molecular pattern (DAMP) protein. We discuss the Janus-faced role of DAMP molecules in inflammation, cancer, and tissue repair. The high-mobility group box (HMGB)-1 and adenosine triphosphate proteins are well-known DAMP molecules and have been primarily associated with inflammation. However, as we shall see, recent data have linked these molecules to tissue repair. HMGB1 is associated with cancer-related inflammation. It activates nuclear factor kB, which is involved in cancer regulation via its receptor for advanced glycation end-products (RAGE), Toll-like receptors 2 and 4. Proinflammatory activity and tissue repair may lead to pharmacologic intervention, by blocking DAMP RAGE and Toll like receptor 2 and 4 role in inflammation and by increasing their concentration in tissue repair, respectively. We conducted a MEDLINE search for articles pertaining to the various issues related to DAMP, and we discuss the most relevant articles especially (ie, not only those published in journals with a higher impact factor). A cluster of remarkable articles on DAMP have appeared in the literature in recent years. Regarding inflammation, several strategies have been proposed to target HMGB1, from antibodies to recombinant box A, which interacts with RAGE, competing with the full molecule. In tissue repair, it was reported that the overexpression of HMGB1 or the administration of exogenous HMGB1 significantly increased the number of vessels and promoted recovery in skin-wound, ischemic injury. Due to the bivalent nature of DAMP, it is often difficult to explain the relative role of DAMP in inflammation versus its role in tissue repair. However, this point is crucial as DAMP-related treatments move into clinical practice.

Gut microbiota regulate intestinal function and health. However, mounting evidence indicates that they can also influence the immune and nervous systems and vice versa. This article reviews the bidirectional relationship between the gut microbiota and the brain, termed the microbiota-gut-brain (MGB) axis, and discusses how it contributes to the pathogenesis of certain disorders that may involve brain inflammation. Articles were identified with a search of Medline (starting in 1980) by using the key words anxiety, attention-deficit hypersensitivity disorder (ADHD), autism, cytokines, depression, gut, hypothalamic–pituitary–adrenal (HPA) axis, inflammation, immune system, microbiota, nervous system, neurologic, neurotransmitters, neuroimmune conditions, psychiatric, and stress. Various afferent or efferent pathways are involved in the MGB axis. Antibiotics, environmental and infectious agents, intestinal neurotransmitters/neuromodulators, sensory vagal fibers, cytokines, and essential metabolites all convey information to the central nervous system about the intestinal state. Conversely, the hypothalamic–pituitary–adrenal axis, the central nervous system regulatory areas of satiety, and neuropeptides released from sensory nerve fibers affect the gut microbiota composition directly or through nutrient availability. Such interactions seem to influence the pathogenesis of a number of disorders in which inflammation is implicated, such as mood disorder, autism-spectrum disorders, attention-deficit hypersensitivity disorder, multiple sclerosis, and obesity. Recognition of the relationship between the MGB axis and the neuroimmune systems provides a novel approach for better understanding and management of these disorders. Appropriate preventive measures early in life or corrective measures such as use of psychobiotics, fecal microbiota transplantation, and flavonoids are discussed.

Vitamin D has been known to be involved in mineral and bone homeostasis for many years. In the past its main use was in treating osteoporosis and rickets. In recent years it was found that vitamin D is an immune-modulating agent and may also have a role in several diseases, including autoimmune diseases. The immune-modulating effects appear to be mediated by vitamin D interaction with the vitamin D receptor (VDR) that has transcriptional effects and is expressed on various cell types, especially those of the immune system. Immunologic and rheumatologic diseases were the first to be studied, but at the moment the spotlight is on the interactions between tumor cells and vitamin D. This review focuses on four forms of cancer that apparently benefit from a vitamin D supplementation during treatment: prostate, breast, and colorectal cancers and melanoma. Several studies reported that differences exist between white and black patients, which we discuss in the review. We systematically searched PubMed for studies published in English. The search terms included vitamin D, cancer, breast, colorectal, prostate, and melanoma. Our findings show that vitamin D has the potential to become a valid coadjuvant in the treatment of cancer.

Fibrosis is a chronic and progressive disorder characterized by excessive deposition of extracellular matrix, which leads to scarring and loss of function of the affected organ or tissue. Indeed, the fibrotic process affects a variety of organs and tissues, with specific molecular background. However, two common hallmarks are shared: the crucial role of the transforming growth factor-beta (TGF-β) and the involvement of the inflammation process, that is essential for initiating the fibrotic degeneration. TGF-β in particular but also other cytokines regulate the most common molecular mechanism at the basis of fibrosis, the Epithelial-to-Mesenchymal Transition (EMT). EMT has been extensively studied, but not yet fully explored as a possible therapeutic target for fibrosis. A deeper understanding of the crosstalk between fibrosis and EMT may represent an opportunity for the development of a broadly effective anti-fibrotic therapy. Here we report the evidences of the relationship between EMT and multi-organ fibrosis, and the possible therapeutic approaches that may be developed by exploiting this relationship.

Tumor tissue is surrounded by mast cells (MCs), which participate in the inflammatory immune response by producing cytokines, proteases, and other molecules. MCs are involved in both innate and acquired immunity and are associated with the IgE response through the FcεRI receptor. MCs mediate inflammation in several immune reactions, including acute hyperreactivity, leukocyte recruitment, acute tissue swelling, anaphylaxis, and pro-inflammatory cytokine production. They not only function as pro-inflammatory effector cells but may also contribute to the regulation of the acquired immune response in tumor tissue. Therefore, MCs may mediate immunity in breast cancer by promoting remodelling and counteracting cancer growth. They also produce anti-inflammatory substances, such as histamine, transforming growth factor-β (TGF-β)1, IL-10, and IL-4, which inhibit the acquired immune response and reduce the inflammatory state. IL-37 and IL-38 are novel natural regulators of inflammation and are anti-inflammatory members of the IL-1 family. IL-1, generated by immune cells such as macrophages and lymphocytes, is released downstream of oncogenes in breast cancer, triggering an inflammatory response by stimulating other pro-inflammatory cytokines such as IL-6, tumor necrosis factor (TNF), and IL-33 (an early warning cytokine). Therefore, blocking IL-1 with IL-37 or IL-38 could represent a novel therapeutic strategy that, when combined with other treatments, could be beneficial in breast cancer. This review focuses on the new discoveries and insights into the role of MCs in breast cancer. We also analyzed molecules that can promote tumor growth and those that can inhibit cancer development and metastasis. This review aims to study the role of MCs accumulated in the stroma of breast adenocarcinoma in relation to secreted anti-inflammatory cytokines, such as IL-37 and IL-38.

Inflammation is a process that plays an important role in the initiation and progression of atherosclerosis and immune disease, involving multiple cell types, including macrophages, T-lymphocytes, endothelial cells, smooth muscle cells and mast cells. The fundamental damage of atherosclerosis is the atheromatous or fibro-fatty plaque which is a lesion that causes several diseases. In atherosclerosis the innate immune response, which involves macrophages, is initiated by the arterial endothelial cells which respond to modified lipoproteins and lead to Th1 cell subset activation and generation of inflammatory cytokines and chemoattractant chemokines. Other immune cells, such as CD4+ T inflammatory cells, which play a critical role in the development and progression of atherosclerosis, and regulatory T cells [Treg], which have a protective effect on the development of atherosclerosis are involved. Considerable evidence indicates that mast cells and their products play a key role in inflammation and atherosclerosis. Activated mast cells can have detrimental effects, provoking matrix degradation, apoptosis, and enhancement as well as recruitment of inflammatory cells, which actively contributes to atherosclerosis and plaque formation. Here we discuss the relationship between atherosclerosis, inflammation and mast cells.

The peptide substance P (SP) has been implicated in inflammatory conditions, such as psoriasis, where mast cells and VEGF are increased. A relationship between SP and VEGF has not been well studied, nor has any interaction with the proinflammatory cytokines, especially IL-33. Here we report that SP (0.1-10 μM) induces gene expression and secretion of VEGF from human LAD2 mast cells and human umbilical core blood-derived cultured mast cells (hCBMCs). This effect is significantly increased by coadministration of IL-33 (5-100 ng/mL) in both cell types. The effect of SP on VEGF release is inhibited by treatment with the NK-1 receptor antagonist 733,060. SP rapidly increases cytosolic calcium, and so does IL-33 to a smaller extent; the addition of IL-33 augments the calcium increase. SP-induced VEGF production involves calcium-dependent PKC isoforms, as well as the ERK and JNK MAPKs. Gene expression of IL-33 and histidine decarboxylase (HDC), an indicator of mast cell presence/activation, is significantly increased in affected and unaffected (at least 15 cm away from the lesion) psoriatic skin, as compared with normal control skin. Immunohistochemistry indicates that IL-33 is associated with endothelial cells in both the unaffected and affected sites, but is stronger and also associated with immune cells in the affected site. These results imply that functional interactions among SP, IL-33, and mast cells leading to VEGF release contribute to inflammatory conditions, such as the psoriasis, a nonallergic hyperproliferative skin inflammatory disorder with a neurogenic component.

Much evidence suggests autoimmunity in the etiopathogenesis of periodontal disease. In fact, in periodontitis, there is antibody production against collagen, DNA, and IgG, as well as increased IgA expression, T cell dysfunction, high expression of class II MHC molecules on the surface of gingival epithelial cells in inflamed tissues, activation of NK cells, and the generation of antibodies against the azurophil granules of polymorphonuclear leukocytes. In general, direct activation of autoreactive immune cells and production of TNF can activate neutrophils to release pro-inflammatory enzymes with tissue damage in the gingiva. Gingival inflammation and, in the most serious cases, periodontitis, are mainly due to the dysbiosis of the commensal oral microbiota that triggers the immune system. This inflammatory pathological state can affect the periodontal ligament, bone, and the entire gingival tissue. Oral tolerance can be abrogated by some cytokines produced by epithelial cells and activated immune cells, including mast cells (MCs). Periodontal cells and inflammatory–immune cells, including mast cells (MCs), produce cytokines and chemokines, mediating local inflammation of the gingival, along with destruction of the periodontal ligament and alveolar bone. Immune-cell activation and recruitment can be induced by inflammatory cytokines, such as IL-1, TNF, IL-33, and bacterial products, including lipopolysaccharide (LPS). IL-1 and IL-33 are pleiotropic cytokines from members of the IL-1 family, which mediate inflammation of MCs and contribute to many key features of periodontitis and other inflammatory disorders. IL-33 activates several immune cells, including lymphocytes, Th2 cells, and MCs in both innate and acquired immunological diseases. The classic therapies for periodontitis include non-surgical periodontal treatment, surgery, antibiotics, anti-inflammatory drugs, and surgery, which have been only partially effective. Recently, a natural cytokine, IL-37, a member of the IL-1 family and a suppressor of IL-1b, has received considerable attention for the treatment of inflammatory diseases. In this article, we report that IL-37 may be an important and effective therapeutic cytokine that may inhibit periodontal inflammation. The purpose of this paper is to study the relationship between MCs, IL-1, IL-33, and IL-37 inhibition in acute and chronic inflamed gingival tissue.

Polyphenols are ubiquitous in food and have long been recognized to possess antioxidant, anti-inflammatory and anticancer activities. Mast cells (MCs) are implicated in the pathogenesis of inflammatory diseases, allergy, autoimmunity and cancer. MCs derive from hematopoietic progenitor cells, reside virtually in all vascularized tissue and are activated by crosslinking of FceRI-bound IgE (at very high affinity: 1 × 1010 M-1) with multivalent antigen. MCs in cytoplasmic granules release preformed chemical mediators, and also they can release lipid mediators and cytokines/chemokines without degranulation. Luteolin, 3’,4’,5,7-tetrahydroxyflavone, is a flavonoid contained in many kinds of plants including vegetables and fruits. This anti-oxidant product inhibits interleukin (IL)-6, IL-8 and vascular endothelial growth factor (VEGF) production from tumor necrosis factor (TNF)-triggered keratinocytes, and is a candidate for use in alternative therapies in the treatment of inflammatory skin disorders. Quercetin (3,3’,4’,5,7-pentahydroxyflavone) is a ubiquitous flavonoid which exhibits anti-cancer, anti-oxidative and anti-inflammatory properties and causes a reduction in the availability of nitrite that influences vascular function. Quercetin exerts physiological functions though the interaction with phosphatidylinositol-3-phosphate kinase (PI3K), mitogen-activated protein kinase (MAPK), extracellular signal regulated kinase (ERK), kinase (MEK) 1, and others, and has a negative effect on FceRI cross-linking and other activating receptors on mast cells. In this article we report for the first time the interrelationship between mast cells and polyphenols.

The biological history of Chlamydia trachomatis is intertwined with the evolution of the man. Infecting Elemental Bodies (EBs), having penetrated mucosal epithelial cells, wrap themselves in a cloak (ĸλαμις) of glycogen that ensures their obligatory intracellular survival and protects this differentiation into Reticulate Bodies (RBs) that feed on cellular ATP. Multiple chemokines and cytokines are involved under the direction of IL-6 in the florid phase and IL-17A in the scar phase. The WHO has successfully identified the SAFE strategy against trachoma (Surgery, Antibiotics, Facial cleansing, Environment) as the blueprint to eliminate the disease by 2020. Recently, interest has been increasingly focused on changing sexual attitudes in different areas of the world, leaving Musca sorbens, Scatophaga stercoraria, and stepsisters fairly blameless, but extolling the role of Chlamydia trachomatis in apparently “sterile” chronic prostatitis or conjunctivitis or, less frequently, in oropharyngitis and proctitis. The addition of an S (SAFE-S) standing for “sexual behavior” was then proposed to also attract the interest and attention not only of Ophthalmologists and Obstetricians/Gynecologists, Urologists/Andrologists, and the School Authorities for information on the prevention of sexually transmitted diseases, but also of Social Physicians and Pediatricians. This means that sexually transmitted infections should be screened in asymptomatic patients with risky sexual behavior or sexual contact with people diagnosed with a transmitted infection.