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Digestion 2023The specific etiopathogenesis of inflammatory bowel disease (IBD) is still unknown. Although the conventional anti-inflammatory or immunomodulatory drugs relatively... (Review)
Review
BACKGROUND
The specific etiopathogenesis of inflammatory bowel disease (IBD) is still unknown. Although the conventional anti-inflammatory or immunomodulatory drugs relatively nonspecific to pathogenesis have been quite useful in many cases, elucidating the pathogenesis has gradually facilitated developments of disease-specific therapies for refractory cases in the last 2 decades.
SUMMARY
With a greater understanding of the multiple overactive signaling pathways of the gut mucosal immune response and enhanced leukocyte trafficking, several biological agents or small molecule drugs following the first novel biologic, anti-tumor necrosis factor α (anti-TNFα), have been developed against several modes of action including adhesion molecules, sphingosine-1-phospate receptors, cytokines (IL-12/23, TL1A, and IL-36), Janus kinase (JAK), and phosphodiesterase. Although preceding biological agents have dramatically changed the IBD treatment strategy, many patients still require alternative therapies due to failure or side effects. Newer treatments are now expected to be provided for better efficacy with an improved adverse event profile. In addition, translational studies have highlighted the new therapeutic concepts' potential, including modulation of host-microbiome interactions, stem therapy for perianal fistula, regulation of fibrosis, regulation of the gut-brain axis, and control of previously less targeted immune cells (B cells and innate lymphoid cells). This paper comprehensively reviewed not only the latest already or shortly available therapies but also emerging promising treatments that will be hopefully established in the future for IBD.
KEY MESSAGES
Many kinds of new treatments are available, and promising treatments with new perspectives are expected to emerge for refractory IBD in the future.
Topics: Humans; Immunity, Innate; Lymphocytes; Inflammatory Bowel Diseases; Cytokines; Tumor Necrosis Factor-alpha
PubMed: 36366823
DOI: 10.1159/000527422 -
Cellular & Molecular Immunology May 2020Neutrophils are frontline cells of the innate immune system. These effector leukocytes are equipped with intriguing antimicrobial machinery and consequently display high... (Review)
Review
Neutrophils are frontline cells of the innate immune system. These effector leukocytes are equipped with intriguing antimicrobial machinery and consequently display high cytotoxic potential. Accurate neutrophil recruitment is essential to combat microbes and to restore homeostasis, for inflammation modulation and resolution, wound healing and tissue repair. After fulfilling the appropriate effector functions, however, dampening neutrophil activation and infiltration is crucial to prevent damage to the host. In humans, chemoattractant molecules can be categorized into four biochemical families, i.e., chemotactic lipids, formyl peptides, complement anaphylatoxins and chemokines. They are critically involved in the tight regulation of neutrophil bone marrow storage and egress and in spatial and temporal neutrophil trafficking between organs. Chemoattractants function by activating dedicated heptahelical G protein-coupled receptors (GPCRs). In addition, emerging evidence suggests an important role for atypical chemoattractant receptors (ACKRs) that do not couple to G proteins in fine-tuning neutrophil migratory and functional responses. The expression levels of chemoattractant receptors are dependent on the level of neutrophil maturation and state of activation, with a pivotal modulatory role for the (inflammatory) environment. Here, we provide an overview of chemoattractant receptors expressed by neutrophils in health and disease. Depending on the (patho)physiological context, specific chemoattractant receptors may be up- or downregulated on distinct neutrophil subsets with beneficial or detrimental consequences, thus opening new windows for the identification of disease biomarkers and potential drug targets.
Topics: Animals; Chemotactic Factors; Disease; Health; Humans; Neutrophils; Receptors, Formyl Peptide; Signal Transduction
PubMed: 32238918
DOI: 10.1038/s41423-020-0412-0 -
Nature Reviews. Immunology Jan 2021Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Understanding of the fundamental processes... (Review)
Review
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Understanding of the fundamental processes underlying the versatile clinical manifestations of COVID-19 is incomplete without comprehension of how different immune cells are recruited to various compartments of virus-infected lungs, and how this recruitment differs among individuals with different levels of disease severity. As in other respiratory infections, leukocyte recruitment to the respiratory system in people with COVID-19 is orchestrated by specific leukocyte trafficking molecules, and when uncontrolled and excessive it results in various pathological complications, both in the lungs and in other organs. In the absence of experimental data from physiologically relevant animal models, our knowledge of the trafficking signals displayed by distinct vascular beds and epithelial cell layers in response to infection by SARS-CoV-2 is still incomplete. However, SARS-CoV-2 and influenza virus elicit partially conserved inflammatory responses in the different respiratory epithelial cells encountered early in infection and may trigger partially overlapping combinations of trafficking signals in nearby blood vessels. Here, we review the molecular signals orchestrating leukocyte trafficking to airway and lung compartments during primary pneumotropic influenza virus infections and discuss potential similarities to distinct courses of primary SARS-CoV-2 infections. We also discuss how an imbalance in vascular activation by leukocytes outside the airways and lungs may contribute to extrapulmonary inflammatory complications in subsets of patients with COVID-19. These multiple molecular pathways are potential targets for therapeutic interventions in patients with severe COVID-19.
Topics: Animals; COVID-19; Cell Movement; Cytokines; Epidemics; Humans; Influenza, Human; Leukocytes; Lung; SARS-CoV-2
PubMed: 33214719
DOI: 10.1038/s41577-020-00470-2 -
Trends in Immunology Jun 2019The number of leukocytes circulating in blood in mammals is under circadian control (i.e., ∼24h). We summarize here latest findings on the mechanisms governing... (Review)
Review
The number of leukocytes circulating in blood in mammals is under circadian control (i.e., ∼24h). We summarize here latest findings on the mechanisms governing leukocyte migration from the blood into various organs, focusing on the distinct leukocyte subtype- and tissue-specific molecules involved. We highlight the oscillatory expression patterns of adhesion molecules, chemokines, and their receptors that are expressed on endothelial cells and leukocytes, and which are crucial regulators of rhythmic leukocyte recruitment. We also discuss the relevance of clock genes for leukocyte function and migration. Finally, we compare immune cell rhythms under steady-state conditions as well as during inflammation and disease, and we postulate how these findings provide potential new avenues for therapeutic intervention.
Topics: Adaptive Immunity; Animals; Chemotaxis, Leukocyte; Circadian Rhythm; Disease Susceptibility; Homeostasis; Humans; Immunity, Innate; Immunomodulation; Leukocytes; Organ Specificity; Time Factors
PubMed: 31109762
DOI: 10.1016/j.it.2019.03.010 -
Trends in Immunology Jul 2018Carbohydrates, or glycans, are as integral to biology as nucleic acids and proteins. In immunology, glycans are well known to drive diverse functions ranging from... (Review)
Review
Carbohydrates, or glycans, are as integral to biology as nucleic acids and proteins. In immunology, glycans are well known to drive diverse functions ranging from glycosaminoglycan-mediated chemokine presentation and selectin-dependent leukocyte trafficking to the discrimination of self and non-self through the recognition of sialic acids by Siglec (sialic acid-binding Ig-like lectin) receptors. In recent years, a number of key immunological discoveries are driving a renewed and burgeoning appreciation for the importance of glycans. In this review, we highlight these findings which collectively help to define and refine our knowledge of the function and impact of glycans within the immune response.
Topics: Animals; Chemokines; Humans; Immunity; Leukocytes; Polysaccharides; Sialic Acid Binding Immunoglobulin-like Lectins
PubMed: 29759949
DOI: 10.1016/j.it.2018.04.004 -
Frontiers in Immunology 2019
Topics: Blood Platelets; Cell Movement; Disease; Homeostasis; Inflammation; Leukocytes; Macrophages
PubMed: 31736975
DOI: 10.3389/fimmu.2019.02560 -
Gastroenterology Feb 2016Leukocyte trafficking to the small and large intestines is tightly controlled to maintain intestinal immune homeostasis, mediate immune responses, and regulate... (Review)
Review
Leukocyte trafficking to the small and large intestines is tightly controlled to maintain intestinal immune homeostasis, mediate immune responses, and regulate inflammation. A wide array of chemoattractants, chemoattractant receptors, and adhesion molecules expressed by leukocytes, mucosal endothelium, epithelium, and stromal cells controls leukocyte recruitment and microenvironmental localization in intestine and in the gut-associated lymphoid tissues (GALTs). Naive lymphocytes traffic to the gut-draining mesenteric lymph nodes where they undergo antigen-induced activation and priming; these processes determine their memory/effector phenotypes and imprint them with the capacity to migrate via the lymph and blood to the intestines. Mechanisms of T-cell recruitment to GALT and of T cells and plasmablasts to the small intestine are well described. Recent advances include the discovery of an unexpected role for lectin CD22 as a B-cell homing receptor GALT, and identification of the orphan G-protein-coupled receptor 15 (GPR15) as a T-cell chemoattractant/trafficking receptor for the colon. GPR15 decorates distinct subsets of T cells in mice and humans, a difference in species that could affect translation of the results of mouse colitis models to humans. Clinical studies with antibodies to integrin α4β7 and its vascular ligand mucosal vascular addressin cell adhesion molecule 1 are proving the value of lymphocyte trafficking mechanisms as therapeutic targets for inflammatory bowel diseases. In contrast to lymphocytes, cells of the innate immune system express adhesion and chemoattractant receptors that allow them to migrate directly to effector tissue sites during inflammation. We review the mechanisms for innate and adaptive leukocyte localization to the intestinal tract and GALT, and discuss their relevance to human intestinal homeostasis and inflammation.
Topics: Adaptive Immunity; Animals; Chemotaxis, Leukocyte; Colon; Enteritis; Humans; Immunity, Innate; Immunity, Mucosal; Immunologic Memory; Intestinal Mucosa; Intestine, Small; Leukocytes; Lymphoid Tissue; Signal Transduction
PubMed: 26551552
DOI: 10.1053/j.gastro.2015.10.046 -
The Journal of Experimental Medicine Mar 2022Leukocyte trafficking between blood and tissues is an essential function of the immune system that facilitates humoral and cellular immune responses. Within tissues,... (Review)
Review
Leukocyte trafficking between blood and tissues is an essential function of the immune system that facilitates humoral and cellular immune responses. Within tissues, leukocytes perform surveillance and effector functions via cell motility and migration toward sites of tissue damage, infection, or inflammation. Neurotransmitters that are produced by the nervous system influence leukocyte trafficking around the body and the interstitial migration of immune cells in tissues. Neural regulation of leukocyte dynamics is influenced by circadian rhythms and altered by stress and disease. This review examines current knowledge of neuro-immune interactions that regulate leukocyte migration and consequences for protective immunity against infections and cancer.
Topics: Cell Movement; Chemotaxis, Leukocyte; Circadian Rhythm; Humans; Leukocytes; Models, Immunological; Models, Neurological; Neural Pathways; Neuroimmunomodulation; Sympathetic Nervous System; Tumor Microenvironment
PubMed: 35195682
DOI: 10.1084/jem.20211604 -
Frontiers in Immunology 2019Beta2-integrins are complex leukocyte-specific adhesion molecules that are essential for leukocyte (e.g., neutrophil, lymphocyte) trafficking, as well as for other... (Review)
Review
Beta2-integrins are complex leukocyte-specific adhesion molecules that are essential for leukocyte (e.g., neutrophil, lymphocyte) trafficking, as well as for other immunological processes such as neutrophil phagocytosis and ROS production, and T cell activation. Intriguingly, however, they have also been found to negatively regulate cytokine responses, maturation, and migratory responses in myeloid cells such as macrophages and dendritic cells, revealing new, and unexpected roles of these molecules in immunity. Because of their essential role in leukocyte function, a lack of expression or function of beta2-integrins causes rare immunodeficiency syndromes, Leukocyte adhesion deficiency type I, and type III (LAD-I and LAD-III). LAD-I is caused by reduced or lost expression of beta2-integrins, whilst in LAD-III, beta2-integrins are expressed but dysfunctional because a major integrin cytoplasmic regulator, kindlin-3, is mutated. Interestingly, some LAD-related phenotypes such as periodontitis have recently been shown to be due to an uncontrolled inflammatory response rather than to an uncontrolled infection, as was previously thought. This review will focus on the recent advances concerning the regulation and functions of beta2-integrins in leukocyte trafficking, immune suppression, and immune deficiency disease.
Topics: Animals; CD18 Antigens; Cell Movement; Humans; Immunologic Deficiency Syndromes; Immunosuppression Therapy; Leukocyte-Adhesion Deficiency Syndrome; Leukocytes; Lymphocyte Activation
PubMed: 30837997
DOI: 10.3389/fimmu.2019.00254 -
Frontiers in Immunology 2019Hematopoietic stem cells (HSC) are the most powerful type of adult stem cell found in the body. Hematopoietic stem cells are multipotent and capable of giving rise to... (Review)
Review
Hematopoietic stem cells (HSC) are the most powerful type of adult stem cell found in the body. Hematopoietic stem cells are multipotent and capable of giving rise to all other types of hematopoietic cells found in the organism. A single HSC is capable of regenerating a functional hematopoietic system when transplanted into a recipient. Hematopoietic stem cells reside in the bone marrow in specific multicellular structures called niches. These niches are indispensable for maintaining and regulating HSC numbers and function. It has become increasingly clearer that HSC and their niches can also be regulated by migrating leukocytes. Here we will discuss the composition of murine bone marrow niches and how HSC and their niches are regulated by different types of leukocytes that traffic between the periphery and the niche. Unless otherwise indicated all the studies discussed below were performed in mouse models.
Topics: Animals; Bone Marrow; Cell Movement; Endothelial Progenitor Cells; Hematopoietic Stem Cells; Leukocytes; Macrophages; Mice; Stem Cell Niche; Stromal Cells
PubMed: 30891044
DOI: 10.3389/fimmu.2019.00387