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Mast cells respond to IL-33 released during cell injury by initiating a pro-inflammatory response. During cell injury, for instance induced by mechanical trauma, structural cell types such as epithelial cells release IL-33. Mast cells recognize IL-33 through the T1/ST2 receptor, which initiates MyD88-dependent signaling mechanisms eventually resulting in NFkB activation and the subsequent transcription of several pro-inflammatory genes. Release of cytokines, chemokines, and lipid mediators together initiates a inflammatory response, for instance resulting in neutrophil recruitment, activation and migration of dendritic cells, and polarization of T cells.
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Mast cells have been attributed several functions in both health and disease. Mast cell activation and release of inflammatory mediators are associated with the pathogenesis of several diseases, in particular that of allergic diseases. While the notion of mast cells as important, protective sentinel cells is old, this feature of the cell is not wel...
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IL-33 is elevated in afflicted tissues of patients with mast cell (MC)-dependent chronic allergic diseases. Based on its acute effects on mouse MCs, IL-33 is thought to play a role in the pathogenesis of allergic disease through MC activation. However, the manifestations of prolonged IL-33 exposure on human MC function, which best reflect the condi...
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... assay ( Fig. 3b) and inhibited recombinant IL-33 red driven IL-8 release (Fig. 3c) in HUVECs with a potency approximately tenfold greater than sST2 (Table 1). Mast cells are an important responding cell type of IL-33 and a major source of ST2 in human lung tissue 42,43 . In human blood-derived mast cells, tozorakimab demonstrated potent inhibition of IL-33-driven inflammatory mediators (IL-13, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor and tumour necrosis factor α; Fig. 3d and Table 1; Supplementary Fig. S2a-e). ...
Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and is a promising target for treatment of inflammatory disease. Here, we describe the identification of tozorakimab (MEDI3506), a potent, human anti-IL-33 monoclonal antibody, which can inhibit reduced IL-33 (IL-33red) and oxidized IL-33 (IL-33ox) activities through distinct serum-stimulated 2 (ST2) and receptor for advanced glycation end products/epidermal growth factor receptor (RAGE/EGFR complex) signalling pathways. We hypothesized that a therapeutic antibody would require an affinity higher than that of ST2 for IL-33, with an association rate greater than 10⁷ M⁻¹ s⁻¹, to effectively neutralize IL-33 following rapid release from damaged tissue. An innovative antibody generation campaign identified tozorakimab, an antibody with a femtomolar affinity for IL-33red and a fast association rate (8.5 × 10⁷ M⁻¹ s⁻¹), which was comparable to soluble ST2. Tozorakimab potently inhibited ST2-dependent inflammatory responses driven by IL-33 in primary human cells and in a murine model of lung epithelial injury. Additionally, tozorakimab prevented the oxidation of IL-33 and its activity via the RAGE/EGFR signalling pathway, thus increasing in vitro epithelial cell migration and repair. Tozorakimab is a novel therapeutic agent with a dual mechanism of action that blocks IL-33red and IL-33ox signalling, offering potential to reduce inflammation and epithelial dysfunction in human disease.
... Expressed constitutively by many tissues, including blood vessels, lymphoid tissues, and epithelial cells, IL-33 acts as a ligand for IL-1 receptor-related protein ST2, found on the surface of immune cells such as mast cells and Th2 cells [269][270][271]. Additionally, IL-33 functions as an alarmin, helping mast cells recognize cellular injury and acting as one of the first responders to parasitic invasion [272][273][274]. IL-33 is inherently linked to the hypoxic response via mTOR, a serine/threonine protein kinase that regulates cell growth, proliferation, and metabolism [275,276]. ...
Body tissues are subjected to various oxygenic gradients and fluctuations and hence can become transiently hypoxic. Hypoxia-inducible factor (HIF) is the master transcriptional regulator of the cellular hypoxic response and is capable of modulating cellular metabolism, immune responses, epithelial barrier integrity, and local microbiota. Recent reports have characterized the hypoxic response to various infections. However, little is known about the role of HIF activation in the context of protozoan parasitic infections. Growing evidence suggests that tissue and blood protozoa can activate HIF and subsequent HIF target genes in the host, helping or hindering their pathogenicity. In the gut, enteric protozoa are adapted to steep longitudinal and radial oxygen gradients to complete their life cycle, yet the role of HIF during these protozoan infections remains unclear. This review focuses on the hypoxic response to protozoa and its role in the pathophysiology of parasitic infections. We also discuss how hypoxia modulates host immune responses in the context of protozoan infections.
... As innate immune cells, MCs possess toll-like receptors (TLRs), which can be activated by pathogen-or damage-associated molecular pattern molecules (25) to effect certain MC functions like mediator release, their antigen-presenting cell (APC) capabilities and interaction with dendritic cells (DCs) (34,35) or interaction with other immune cells (18,19). They respond to cell injury independently of TLRs through IL-33 activation and many other mediators (36). As an 'unprofessional' APC they can, in conjunction with DCs, fine-tune a type 2 immune response through promoting DC migration to draining lymph nodes, thereby priming an adequate T helper 2 (Th2) cell response. ...
Mast cells (MCs) are innate immune cells with a versatile set of functionalities, enabling them to orchestrate immune responses in various ways. Aside from their known role in allergy, they also partake in both allograft tolerance and rejection through interaction with regulatory T cells, effector T cells, B cells and degranulation of cytokines and other mediators. MC mediators have both pro- and anti-inflammatory actions, but overall lean towards pro-fibrotic pathways. Paradoxically, they are also seen as having potential protective effects in tissue remodeling post-injury. This manuscript elaborates on current knowledge of the functional diversity of mast cells in kidney transplants, combining theory and practice into a MC model stipulating both protective and harmful capabilities in the kidney transplant setting.
... IgE is thought to have a central role in the activation of mast cells through cross-linking of its high-affinity receptors (FceIRs), whereas non-IgE-mediated activation of mast cells has been regarded as potentially important factor in the initation and amplification of acute inflammatory responses induced by tissue injury (53)(54)(55). DAMPs released from injured tissues, such as ATP (56) and IL-33 (45,57), are recognized by mast cells via their receptors (P2X and P2Y receptors for ATP, ST2 receptor for IL-33), and then recognized DAMPs increase intracellular Ca 2+ and activate mast cell degranulation. C3a and C5a, two complement components, can stimulate mast cell migration and degranulation via C3aRs and C5aRs (58,59). ...
Responding to tissue injury, skeletal muscles undergo the tissue destruction and reconstruction accompanied with inflammation. The immune system recognizes the molecules released from or exposed on the damaged tissue. In the local minor tissue damage, tissue-resident macrophages sequester pro-inflammatory debris to prevent initiation of inflammation. In most cases of the skeletal muscle injury, however, a cascade of inflammation will be initiated through activation of local macrophages and mast cells and recruitment of immune cells from blood circulation to the injured site by recongnization of damage-associated molecular patterns (DAMPs) and activated complement system. During the inflammation, macrophages and neutrophils scavenge the tissue debris to release inflammatory cytokines and the latter stimulates myoblast fusion and vascularization to promote injured muscle repair. On the other hand, an abundance of released inflammatory cytokines and chemokines causes the profound hyper-inflammation and mobilization of immune cells to trigger a vicious cycle and lead to the cytokine storm. The cytokine storm results in the elevation of cytolytic and cytotoxic molecules and reactive oxygen species (ROS) in the damaged muscle to aggravates the tissue injury, including the healthy bystander tissue. Severe inflammation in the skeletal muscle can lead to rhabdomyolysis and cause sepsis-like systemic inflammation response syndrome (SIRS) and remote organ damage. Therefore, understanding more details on the involvement of inflammatory factors and immune cells in the skeletal muscle damage and repair can provide the new precise therapeutic strategies, including attenuation of the muscle damage and promotion of the muscle repair.
... Irrespective of the cause of inflammation (physical, chemical, or biological), tissue-resident cells are the first ones to sense the abnormality in the microenvironment and signals for generating appropriate responses. Neighboring mast cells are the first cells to sense injury and necrotic tissue (Lunderius-Andersson et al, 2012). The role of mast cells in inflammation has been studied extensively (Krystel-Whittemore et al, 2015). ...
There is an increasing need to develop biological anti-inflammatory agents that are more targeted, effective, and with lesser side effects as compared to conventional chemical drugs. In the present study, we found that Mycobacterium tuberculosis protein PPE2 and a synthetic derivative peptide can suppress the mast cell population and inhibit several vasoactive and fibrogenic mediators and pro-inflammatory cytokines induced by mast cells in formalin-induced tissue injury. PPE2 was found to inhibit transcription from the promoter of stem cell factor, important for mast cell maintenance and migration. Thus, PPE2/peptide can be used as a potent nonsteroidal therapeutic agent for the treatment of inflammation and tissue injury.
... The IL-33/ST2 pathway is involved in CNS homeostasis and its pathologies, including neurodegenerative diseases (Sun et al., 2021). Mast cells are a population of IL-33 targeting cells, recognizing it by IL-33 receptor, ST2 (Lunderius-Andersson et al., 2012). Mast cells activation is observed in PD brains and may play role in neuroinflammation in this disease (Kempuraj et al., 2015(Kempuraj et al., , 2019. ...
Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by neuroinflammation, formation of Lewy bodies, and progressive loss of dopaminergic neurons in the substantia nigra of the brain. In this review, we summarize evidence obtained by animal studies demonstrating neuroinflammation as one of the central pathogenetic mechanisms of PD. We also focus on the protein factors that initiate the development of PD and other neurodegenerative diseases. Our targeted literature search identified 40 pre-clinical in vivo and in vitro studies written in English. Nuclear factor kappa B (NF-kB) pathway is demonstrated as a common mechanism engaged by neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA), as well as the bacterial lipopolysaccharide (LPS). The α-synuclein protein, which plays a prominent role in PD neuropathology, may also contribute to neuroinflammation by activating mast cells. Meanwhile, 6-OHDA models of PD identify microsomal prostaglandin E synthase-1 (mPGES-1) as one of the contributors to neuroinflammatory processes in this model. Immune responses are used by the central nervous system to fight and remove pathogens; however, hyperactivated and prolonged immune responses can lead to a harmful neuroinflammatory state, which is one of the key mechanisms in the pathogenesis of PD.
... Multiple proteins control mast cell activation or have been linked to the function of this cell type, including the RAS oncogene family member RAB27A and interleukin 33 (IL33). IL33 is an alarmin cytokine that is released in response to cell injury, infection, or mechanical damage, to induce inflammation [11] through the promotion of mast cells granulation and recruitment to the site of injury [12]. RAB27A inhibits mast cell degranulation and activation [13]. ...
... We further found that NFE2L3 is required for the induction of Il33 transcripts and the reduction of mRNA levels of members of the RAB pathway. These results are relevant as the RAB pathway differentially controls mast secretory granules and IL33 activates mast cells by promoting their granulation and recruitment to the site of injury (Fig. 6a) [12,13]. ...
We investigated the role of the NFE2L3 transcription factor in inflammation-induced colorectal cancer. Our studies revealed that Nfe2l3−/− mice exhibit significantly less inflammation in the colon, reduced tumor size and numbers, and skewed localization of tumors with a more pronounced decrease of tumors in the distal colon. CIBERSORT analysis of RNA-seq data from normal and tumor tissue predicted a reduction in mast cells in Nfe2l3−/− animals, which was confirmed by toluidine blue staining. Concomitantly, the transcript levels of Il33 and Rab27a, both important regulators of mast cells, were reduced and increased, respectively, in the colorectal tumors of Nfe2l3−/− mice. Furthermore, we validated NFE2L3 binding to the regulatory sequences of the IL33 and RAB27A loci in human colorectal carcinoma cells. Using digital spatial profiling, we found that Nfe2l3−/− mice presented elevated FOXP3 and immune checkpoint markers CTLA4, TIM3, and LAG3, suggesting an increase in Treg counts. Staining for CD3 and FOXP3 confirmed a significant increase in immunosuppressive Tregs in the colon of Nfe2l3−/− animals. Also, Human Microbiome Project (HMP2) data showed that NFE2L3 transcript levels are higher in the rectum of ulcerative colitis patients. The observed changes in the tumor microenvironment provide new insights into the molecular differences regarding colon cancer sidedness. This may be exploited for the treatment of early-onset colorectal cancer as this emerging subtype primarily displays distal/left-sided tumors.
... In response to several viral infections the production of chemokines, along with type 1 interferons (IFN) represent the predominant mast cell response and leads to the recruitment of NK cells and CD56+ T cells (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Mast cells also respond to tissue damage via responses to alarmins, such as IL-33, subsequently giving rise to a further unique pattern of mediators including IL-13 and IL-5 (21)(22)(23). While degranulation is induced by certain stimuli, such as nematode parasites and select bacteria, mediator production often occurs in its absence. ...
Mast cells are well known to be activated via cross-linking of immunoglobulins bound to surface receptors. They are also recognized as key initiators and regulators of both innate and adaptive immune responses against pathogens, especially in the skin and mucosal surfaces. Substantial attention has been given to the role of mast cells in regulating T cell function either directly or indirectly through actions on dendritic cells. In contrast, the ability of mast cells to modify B cell responses has been less explored. Several lines of evidence suggest that mast cells can greatly modify B cell generation and activities. Mast cells co-localise with B cells in many tissue settings and produce substantial amounts of cytokines, such as IL-6, with profound impacts on B cell development, class-switch recombination events, and subsequent antibody production. Mast cells have also been suggested to modulate the development and functions of regulatory B cells. In this review, we discuss the critical impacts of mast cells on B cells using information from both clinical and laboratory studies and consider the implications of these findings on the host response to infections.
... IL-33 acts synergistically with IgE to enhance the activity of MCs [50]. IL-33 also signals MCs to produce Th2 cytokines (e.g., IL-5 and IL-13) [51], which are involved in skin inflammation, lower airway inflammation and asthma [52][53][54]. Nonetheless, IL-33 also plays a protective role in worm infection and wound healing [55,56]. TNF α-2β can inhibit the proliferation of MCs [57]. ...
It is well known that mast cells (MCs) initiate type I allergic reactions and inflammation in a quick response to the various stimulants, including—but not limited to—allergens, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs). MCs highly express receptors of these ligands and proteases (e.g., tryptase, chymase) and cytokines (TNF), and other granular components (e.g., histamine and serotonin) and aggravate the allergic reaction and inflammation. On the other hand, accumulated evidence has revealed that MCs also possess immune-regulatory functions, suppressing chronic inflammation and allergic reactions on some occasions. IL-2 and IL-10 released from MCs inhibit excessive immune responses. Recently, it has been revealed that allergen immunotherapy modulates the function of MCs from their allergic function to their regulatory function to suppress allergic reactions. This evidence suggests the possibility that manipulation of MCs functions will result in a novel approach to the treatment of various MCs-mediated diseases.
... In particular, fibroblast function control by a weak inflammatory response due to the immature immune system plays an important role [65]. Adult wound healing is characterised by a mast cell-mediated influx of neutrophils [66] and macrophages, the secretion of cytokines such as Macrophage Colony Stimulating Factor (CSF-1), tumour necrosis factor (TNF-α), and PDGF to induce differentiation from fibroblasts to myofibroblasts, and the acceleration of fibrogenesis [21,67]. In contrast, foetal wound healing has less invasion and maturation of immune cells such as neutrophils, macrophages, and mast cells, which contributes to a weak inflammatory response and reduced scar tissue formation [68]. ...
In the past decade, a new frontier in scarless wound healing has arisen because of significant advances in the field of wound healing realised by incorporating emerging concepts from mechanobiology and immunology. The complete integumentary organ system (IOS) regeneration and scarless wound healing mechanism, which occurs in specific species, body sites and developmental stages, clearly shows that mechanical stress signals and immune responses play important roles in determining the wound healing mode. Advances in tissue engineering technology have led to the production of novel human skin equivalents and organoids that reproduce cell–cell interactions with tissue-scale tensional homeostasis, and enable us to evaluate skin tissue morphology, functionality, drug response and wound healing. This breakthrough in tissue engineering has the potential to accelerate the understanding of wound healing control mechanisms through complex mechanobiological and immunological interactions. In this review, we present an overview of recent studies of biomechanical and immunological wound healing and tissue remodelling mechanisms through comparisons of species- and developmental stage-dependent wound healing mechanisms. We also discuss the possibility of elucidating the control mechanism of wound healing involving mechanobiological and immunological interaction by using next-generation human skin equivalents.
