Psoriasis is a chronic inflammatory disease of the skin that affects about 2–3% of the population and greatly impairs the quality of life of affected individuals. Psoriatic skin is characterized by ...excessive proliferation and aberrant differentiation of keratinocytes, as well as redness caused by increased dilation of the dermal blood vessels and infiltration of immune cells. Although the pathogenesis of psoriasis has not yet been completely elucidated, it is generally believed to arise from a complex interplay between hyperproliferating keratinocytes and infiltrating, activated immune cells. So far, the exact triggers that elicit this disease are still enigmatic, yet, it is clear that genetic predisposition significantly contributes to the development of psoriasis. In this review, we summarize current knowledge of important cellular and molecular mechanisms driving the initiation and amplification stages of psoriasis development, with a particular focus on cytokines and emerging evidence illustrating keratinocyte-intrinsic defects as key drivers of inflammation. We also discuss mouse models that have contributed to a better understanding of psoriasis pathogenesis and the preclinical development of novel therapeutics, including monoclonal antibodies against specific cytokines or cytokine receptors that have revolutionized the treatment of psoriasis. Future perspectives that may have the potential to push basic research and open up new avenues for therapeutic intervention are provided.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Recognition of microbial pathogens and dead cells and their phagocytic uptake by specialized immune cells are essential to maintain host homeostasis. Phagosomes undergo fusion and fission events with ...endosomal and lysosomal compartments, a process called ‘phagosome maturation’, which leads to the degradation of the phagosomal content. However, many phagocytic cells also act as antigen-presenting cells and must balance degradation and peptide preservation. Emerging evidence indicates that receptor engagement by phagosomal cargo, as well as inflammatory mediators and cellular activation affect many aspects of phagosome maturation. Unsurprisingly, pathogens have developed strategies to hijack this machinery, thereby interfering with host immunity. Here, we highlight progress in this field, summarize findings on the impact of immune signals, and discuss consequences for pathogen elimination.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Members of the extended interleukin-1 (IL-1) cytokine family, such as IL-1, IL-18, IL-33, and IL-36, play a pivotal role in the initiation and amplification of immune responses. However, deregulated ...production and/or activation of these cytokines can lead to the development of multiple inflammatory disorders. IL-1 family members share a broadly similar domain organization and receptor signaling pathways. Another striking similarity between IL-1 family members is the requirement for proteolytic processing in order to unlock their full biological potential. Although much emphasis has been put on the role of caspase-1, another emerging theme is the involvement of neutrophil- and mast cell-derived proteases in IL-1 family cytokine processing. Elucidating the regulation of IL-1 family members by proteolytic processing is of great interest for understanding inflammation and immunity. Here, we review the identity of the proteases involved in the proteolytic processing of IL-1 family cytokines and the therapeutic implications in inflammatory disease.
The members of the interleukin-1 family of cytokines are soluble mediators of inflammation. They are frequently synthesized as inactive “pro-forms” that require proteolytic processing for their bioactivity. In this review, Beyaert and colleagues survey the literature and provide a comprehensive synopsis of the role of proteases in activation of IL-1 family member cytokines.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abscisic acid (ABA) is a sesquiterpene signaling molecule produced in all kingdoms of life. To date, the best known functions of ABA are derived from its role as a major phytohormone in plant abiotic ...stress resistance. Different organisms have developed different biosynthesis and signal transduction pathways related to ABA. Despite this, there are also intriguing common themes where ABA often suppresses host immune responses and is utilized by pathogens as an effector molecule. ABA also seems to play an important role in compatible mutualistic interactions such as mycorrhiza and rhizosphere bacteria with plants, and possibly also the animal gut microbiome. The frequent use of ABA in inter-species communication could be a possible reason for the wide distribution and re-invention of ABA as a signaling molecule in different organisms. In humans and animal models, it has been shown that ABA treatment or nutrient-derived ABA is beneficial in inflammatory diseases like colitis and type 2 diabetes, which confer potential to ABA as an interesting nutraceutical or pharmacognostic drug. The anti-inflammatory activity, cellular metabolic reprogramming, and other beneficial physiological and psychological effects of ABA treatment in humans and animal models has sparked an interest in this molecule and its signaling pathway as a novel pharmacological target. In contrast to plants, however, very little is known about the ABA biosynthesis and signaling in other organisms. Genes, tools and knowledge about ABA from plant sciences and studies of phytopathogenic fungi might benefit biomedical studies on the physiological role of endogenously generated ABA in humans.
A20: Central Gatekeeper in Inflammation and Immunity Coornaert, Beatrice; Carpentier, Isabelle; Beyaert, Rudi
Journal of biological chemistry/The Journal of biological chemistry,
03/2009, Volume:
284, Issue:
13
Journal Article
Peer reviewed
Open access
Inappropriate functioning of the immune system is linked to immune deficiency, autoimmune disease, and cancer. It is therefore not surprising that intracellular immune signaling pathways are tightly ...controlled. One of the best studied transcription factors in immune signaling is NF-κB, which is activated by multiple receptors and regulates the expression of a wide variety of proteins that control innate and adaptive immunity. A20 is an early NF-κB-responsive gene that encodes a ubiquitin-editing protein that is involved in the negative feedback regulation of NF-κB signaling. Here, we discuss the mechanism of action of A20 and its role in the regulation of inflammation and immunity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Prostate cancer is a highly prevalent form of cancer that is usually slow-developing and benign. Due to its high prevalence, it is, however, still the second most common cause of death by cancer in ...men in the West. The higher prevalence of prostate cancer in the West might be due to elevated inflammation from metabolic syndrome or associated comorbidities. NF-κB activation and many other signals associated with inflammation are known to contribute to prostate cancer malignancy. Inflammatory signals have also been associated with the development of castration resistance and resistance against other androgen depletion strategies, which is a major therapeutic challenge. Here, we review the role of inflammation and its link with androgen signaling in prostate cancer. We further describe the role of NF-κB in prostate cancer cell survival and proliferation, major NF-κB signaling pathways in prostate cancer, and the crosstalk between NF-κB and androgen receptor signaling. Several NF-κB-induced risk factors in prostate cancer and their potential for therapeutic targeting in the clinic are described. A better understanding of the inflammatory mechanisms that control the development of prostate cancer and resistance to androgen-deprivation therapy will eventually lead to novel treatment options for patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background Chronic airway inflammatory diseases, such as chronic rhinosinusitis with nasal polyps and asthma, show increased nasal Staphylococcus aureus colonization. Staphylococcus aureus –derived ...serine protease–like protein (Spl) D and other closely related proteases secreted by S aureus have recently been identified as inducers of allergic asthma in human subjects and mice, but their mechanism of action is largely unknown. Objective We investigated the role of recombinant SplD in driving TH 2-biased responses and IgE formation in a murine model of allergic asthma. Methods Allergic asthma was induced in C57BL/6 J wild-type mice, Toll-like receptor (TLR) 4 knockout (Tlr4 −/− ) mice, and recombination-activating gene (Rag2) knockout (Rag2 −/− ) mice by means of repeated intratracheal applications of SplD. Inflammatory parameters in the airways were assessed by means of flow cytometry, ELISA, Luminex, and immunohistochemistry. Serum SplD-specific IgE levels were analyzed by using ELISA. Results We observed that repeated intratracheal exposure to SplD led to IL-33 and eotaxin production, eosinophilia, bronchial hyperreactivity, and goblet cell hyperplasia in the airways. Blocking IL-33 activity with a soluble ST2 receptor significantly decreased the numbers of eosinophils, IL-13+ type 2 innate lymphoid cells and IL-13+ CD4+ T cells and IL-5 and IL-13 production by lymph node cells but had no effect on IgE production. SplD-induced airway inflammation and IgE production were largely dependent on the presence of the functional adaptive immune system and independent of TLR4 signaling. Conclusion The S aureus –derived protein SplD is a potent allergen of S aureus and induces a TH 2-biased inflammatory response in the airways in an IL-33–dependent but TRL4-independent manner. The soluble ST2 receptor could be an efficient strategy to interfere with SplD-induced TH 2 inflammation but does not prevent the allergic sensitization.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Allergic disease originates in early life and polymorphisms in interleukin-33 gene (IL33) and IL1RL1, coding for IL-33R and decoy receptor sST2, confer allergy risk. Early life T helper 2 (Th2) cell ...skewing and allergy susceptibility are often seen as remnants of feto-maternal symbiosis. Here we report that shortly after birth, innate lymphoid type 2 cells (ILC2s), eosinophils, basophils, and mast cells spontaneously accumulated in developing lungs in an IL-33-dependent manner. During the phase of postnatal lung alveolarization, house dust mite exposure further increased IL-33, which boosted cytokine production in ILC2s and activated CD11b+ dendritic cells (DCs). IL-33 suppressed IL-12p35 and induced OX40L in neonatal DCs, thus promoting Th2 cell skewing. Decoy sST2 had a strong preventive effect on asthma in the neonatal period, less so in adulthood. Thus, enhanced neonatal Th2 cell skewing to inhaled allergens results from postnatal hyperactivity of the IL-33 axis during a period of maximal lung remodeling.
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•There is spontaneous accumulation of type 2 immune cells in the developing lung•Perinatal type 2 immunity depends on IL-33 and not on T or B cells•Postnatal lung DCs are very scarce yet very efficient at inducing Th2 cell adaptive immunity•The IL-33 axis is more important for asthma development at young age
It is not known why allergy often begins in early life. de Kleer et al. show that shortly after birth, type 2 innate immune cells accumulate in an IL-33-dependent manner in the developing lung. Interleukin-33 furthermore boosts the function of neonatal dendritic cells to promote long-lasting Th2-cell-mediated immunity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
MALT1 is a signaling protein that plays a key role in immunity, inflammation, and lymphoid malignancies. For a long time MALT1 was believed to function as a scaffold protein, providing an assembly ...platform for other signaling proteins. This view changed dramatically when MALT1 was also found to have proteolytic activity and a capacity to fine-tune immune responses. Preclinical studies have fostered the belief that MALT1 is a promising therapeutic target in autoimmunity and B cell lymphomas. However, recent studies have shown that mice expressing catalytically-inactive MALT1 develop multi-organ inflammation and autoimmunity, and thus have tempered this initial enthusiasm. We discuss recent findings, highlighting the urgent need for a better mechanistic and functional understanding of MALT1 in host defense and disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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