The mammalian immune system effectively fights infection through the cooperation of two connected systems, innate and adaptive immunity. Germ-line encoded pattern recognition receptors (PRRs) of the ...innate immune system sense the presence of infection and activate innate immunity. Some PRRs also induce signals that lead to the activation of adaptive immunity. Adaptive immunity is controlled by PRR-induced signals at multiple checkpoints dictating the initiation of a response, the type of response, the magnitude and duration of the response, and the production of long-term memory. PRRs thus instruct the adaptive immune system on when and how to best respond to a particular infection. In this review, we discuss the roles of various PRRs in control of adaptive immunity.
The intestinal mucosal barrier controlling the resident microbiome is dependent on a protective mucus layer generated by goblet cells, impairment of which is a hallmark of the inflammatory bowel ...disease, ulcerative colitis. Here, we show that IL-18 is critical in driving the pathologic breakdown of barrier integrity in a model of colitis. Deletion of Il18 or its receptor Il18r1 in intestinal epithelial cells (Δ/EC) conferred protection from colitis and mucosal damage in mice. In contrast, deletion of the IL-18 negative regulator Il18bp resulted in severe colitis associated with loss of mature goblet cells. Colitis and goblet cell loss were rescued in Il18bp−/−;Il18rΔ/EC mice, demonstrating that colitis severity is controlled at the level of IL-18 signaling in intestinal epithelial cells. IL-18 inhibited goblet cell maturation by regulating the transcriptional program instructing goblet cell development. These results inform on the mechanism of goblet cell dysfunction that underlies the pathology of ulcerative colitis.
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•IL-18/IL-18R signaling in intestinal epithelial cells promotes DSS-induced colitis•Hyperactive epithelial IL-18 signaling drives goblet cell depletion during colitis•Epithelial IL-18 signaling prevents goblet cell maturation prior to colitis•IL-18 intercepts the transcriptional program controlling goblet cell development
Production of the cytokine IL-18 by epithelial cells, previously thought to protect the mucosal barrier from the effect of inflammation, is critical to drive the pathologic breakdown of intestinal barrier integrity, directly inhibiting goblet cell maturation prior to the onset of colitis.
•Secretory immunoglobulin A (SIgA) is the dominant antibody at mucosal surfaces.•Gut commensals are coated by SIgA at varied levels.•SIgA targeting regulates bacterial activities and shapes gut ...microbiota composition.•SIgA enforces host-microbiota homeostasis throughout the lifespan.
The trillions of microbes that constitutively colonize the intestine (the gut microbiota) impact diverse aspects of human physiology in health and disease. Immunoglobulin A (IgA) is the most abundant antibody isotype produced at mucosal surfaces, and nearly two grams of IgA is secreted into the intestine every day. Secretory IgA (SIgA) provides critical protection against pathogens and toxins, but can also directly bind to and ‘coat’ commensal bacteria in the gut. Commensal targeting by SIgA shapes gut microbiota composition, modulates bacterial behaviors, and enforces host-microbiota homeostasis in both mice and humans.
Venoms consist of toxic components that are delivered to their victims via bites or stings. Venoms also represent a major class of allergens in humans. Phospholipase A2 (PLA2) is a conserved ...component of venoms from multiple species and is the major allergen in bee venom. Here we examined how bee venom PLA2 is sensed by the innate immune system and induces a type 2 immune response in mice. We found that bee venom PLA2 induced a T helper type 2 (Th2) cell-type response and group 2 innate lymphoid cell activation via the enzymatic cleavage of membrane phospholipids and release of interleukin-33. Furthermore, we showed that the IgE response to PLA2 could protect mice from future challenge with a near-lethal dose of PLA2. These data suggest that the innate immune system can detect the activity of a conserved component of venoms and induce a protective immune response against a venom toxin.
•PLA2 induces IL-33 release and Th2 and ILC2 activation•PLA2 from both bee and snake venoms induces Th2 cell-type responses•ST2-deficient mice exhibit diminished Th2 cell and ILC2 responses to bvPLA2•FcεR1α contributes to protection from bvPLA2 toxicity
The initiation of type 2 immune responses by the epithelial cell-derived cytokines IL-25, IL-33 and TSLP has been an area of extensive research in the past decade. Such studies have led to the ...identification of a new innate lymphoid subset that produces the canonical type 2 cytokines IL-5, IL-9 and IL-13 in response to IL-25 and IL-33. These group 2 or type 2 innate lymphoid cells (ILC2 cells) represent a critical source of type 2 cytokines in vivo and serve an important role in orchestrating the type 2 response to helminths and allergens. Further characterization of ILC2 cell biology will enhance the understanding of type 2 responses and may identify new treatments for asthma, allergies and parasitic infections. Interactions between ILC2 cells and the adaptive immune system, as well as examination of potential roles for ILC2 cells in the maintenance of homeostasis, promise to be particularly fruitful areas of future research.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Acute psychological stress has long been known to decrease host fitness to inflammation in a wide variety of diseases, but how this occurs is incompletely understood. Using mouse models, we show that ...interleukin-6 (IL-6) is the dominant cytokine inducible upon acute stress alone. Stress-inducible IL-6 is produced from brown adipocytes in a beta-3-adrenergic-receptor-dependent fashion. During stress, endocrine IL-6 is the required instructive signal for mediating hyperglycemia through hepatic gluconeogenesis, which is necessary for anticipating and fueling “fight or flight” responses. This adaptation comes at the cost of enhancing mortality to a subsequent inflammatory challenge. These findings provide a mechanistic understanding of the ontogeny and adaptive purpose of IL-6 as a bona fide stress hormone coordinating systemic immunometabolic reprogramming. This brain-brown fat-liver axis might provide new insights into brown adipose tissue as a stress-responsive endocrine organ and mechanistic insight into targeting this axis in the treatment of inflammatory and neuropsychiatric diseases.
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•IL-6 is the dominant endocrine cytokine induced by acute stress in mice•Stress-inducible IL-6 is produced in brown adipocytes via ADRB3 signaling•IL-6 is required for stress hyperglycemia and adaptive “fight or flight” responses•Stress-induced IL-6 decreases tolerance to a subsequent inflammatory challenge
During acute psychological stress, brown adipocytes initiate a chain of events mediated by adrenergic signaling and IL-6 release that metabolically fuels “fight or flight” adaptive responses but at the same time comes at an inflammatory cost.
Specific members of the intestinal microbiota dramatically affect inflammatory bowel disease (IBD) in mice. In humans, however, identifying bacteria that preferentially affect disease susceptibility ...and severity remains a major challenge. Here, we used flow-cytometry-based bacterial cell sorting and 16S sequencing to characterize taxa-specific coating of the intestinal microbiota with immunoglobulin A (IgA-SEQ) and show that high IgA coating uniquely identifies colitogenic intestinal bacteria in a mouse model of microbiota-driven colitis. We then used IgA-SEQ and extensive anaerobic culturing of fecal bacteria from IBD patients to create personalized disease-associated gut microbiota culture collections with predefined levels of IgA coating. Using these collections, we found that intestinal bacteria selected on the basis of high coating with IgA conferred dramatic susceptibility to colitis in germ-free mice. Thus, our studies suggest that IgA coating identifies inflammatory commensals that preferentially drive intestinal disease. Targeted elimination of such bacteria may reduce, reverse, or even prevent disease development.
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•Bacterial members of the intestinal microbiota are differentially coated with IgA•A limited number of intestinal bacterial species are highly coated with IgA•IgA coating defines a subset of bacteria that selectively stimulates intestinal immunity•High IgA coating marks colitogenic bacteria in inflammatory bowel disease
A method termed as immunoglobulin A coating can be applied to distinguish and potentially target bacteria that are potential drivers of inflammatory bowel disease from the remaining members of the microbiota.
The trillions of bacteria that constitutively colonize the human gut collectively generate thousands of unique small molecules. These microbial metabolites can accumulate both locally and ...systemically and potentially influence nearly all aspects of mammalian biology, including immunity, metabolism, and even mood and behavior. In this review, we briefly summarize recent work identifying bioactive microbiota metabolites, the means through which they are synthesized, and their effects on host physiology. Rather than offering an exhaustive list of all known bioactive microbial small molecules, we select a few examples from each key class of metabolites to illustrate the diverse impacts of microbiota-derived compounds on the host. In addition, we attempt to address the microbial logic behind specific biotransformations. Finally, we outline current and emerging strategies for identifying previously undiscovered bioactive microbiota metabolites that may shape human health and disease.
Allergies are generally thought to be a detrimental outcome of a mistargeted immune response that evolved to provide immunity to macroparasites. Here we present arguments to suggest that allergic ...immunity has an important role in host defence against noxious environmental substances, including venoms, haematophagous fluids, environmental xenobiotics and irritants. We argue that appropriately targeted allergic reactions are beneficial, although they can become detrimental when excessive. Furthermore, we suggest that allergic hypersensitivity evolved to elicit anticipatory responses and to promote avoidance of suboptimal environments.
Direct recognition of invading pathogens by innate immune cells is a critical driver of the inflammatory response. However, cells of the innate immune system can also sense their local ...microenvironment and respond to physiological fluctuations in temperature, pH, oxygen and nutrient availability, which are altered during inflammation. Although cells of the immune system experience force and pressure throughout their life cycle, little is known about how these mechanical processes regulate the immune response. Here we show that cyclical hydrostatic pressure, similar to that experienced by immune cells in the lung, initiates an inflammatory response via the mechanically activated ion channel PIEZO1. Mice lacking PIEZO1 in innate immune cells showed ablated pulmonary inflammation in the context of bacterial infection or fibrotic autoinflammation. Our results reveal an environmental sensory axis that stimulates innate immune cells to mount an inflammatory response, and demonstrate a physiological role for PIEZO1 and mechanosensation in immunity.
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