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Cell Reports Sep 2023Emerging evidence suggests that peripheral immune cells contribute to Alzheimer's disease (AD) neuropathogenesis. Among these, mast cells are known for their functions...
Emerging evidence suggests that peripheral immune cells contribute to Alzheimer's disease (AD) neuropathogenesis. Among these, mast cells are known for their functions in allergic reactions and neuroinflammation; however, little is known about their role in AD. Here, we crossed 5XFAD mice with mast cell-deficient strains and observed the effects on AD-related neuropathology and cognitive impairment. We found that mast cell depletion improved contextual fear conditioning in 5XFAD mice without affecting cued fear conditioning, anxiety-like behavior, or amyloid burden. Furthermore, mast cell depletion led to an upregulation of transcriptomic signatures for putatively protective disease-associated microglia and resulted in reduced markers indicative of reactive astrocytes. We hypothesize a system of bidirectional communication between dural mast cells and the brain, where mast cells respond to signals from the brain environment by expressing immune-regulatory mediators, impacting cognition and glial cell function. These findings highlight mast cells as potential therapeutic targets for AD.
Topics: Mice; Animals; Microglia; Mast Cells; Mice, Transgenic; Alzheimer Disease; Cognition; Immunologic Factors
PubMed: 37713312
DOI: 10.1016/j.celrep.2023.113141 -
Nature Aug 2023The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with...
The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance. Here, we show that antigen-specific avoidance behaviour in inbred mice is critically dependent on mast cells; hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity.
Topics: Animals; Mice; Allergens; Avoidance Learning; Hypersensitivity; Immunoglobulin E; Mast Cells; Stomach; Vagotomy; Immunity, Innate; Immunity, Mucosal; Th2 Cells; Cytokines; Leukotrienes; Intestine, Small
PubMed: 37438525
DOI: 10.1038/s41586-023-06188-0 -
The Journal of Experimental Medicine Oct 2023Mast cells (MCs) are tissue-resident immune cells that exhibit homeostatic and neuron-associated functions. Here, we combined whole-tissue imaging and single-cell RNA...
Mast cells (MCs) are tissue-resident immune cells that exhibit homeostatic and neuron-associated functions. Here, we combined whole-tissue imaging and single-cell RNA sequencing datasets to generate a pan-organ analysis of MCs in mice and humans at steady state. In mice, we identify two mutually exclusive MC populations, MrgprB2+ connective tissue-type MCs and MrgprB2neg mucosal-type MCs, with specific transcriptomic core signatures. While MrgprB2+ MCs develop in utero independently of the bone marrow, MrgprB2neg MCs develop after birth and are renewed by bone marrow progenitors. In humans, we unbiasedly identify seven MC subsets (MC1-7) distributed across 12 organs with different transcriptomic core signatures. MC1 are preferentially enriched in the bladder, MC2 in the lungs, and MC4, MC6, and MC7 in the skin. Conversely, MC3 and MC5 are shared by most organs but not skin. This comprehensive analysis offers valuable insights into the natural diversity of MC subtypes in both mice and humans.
Topics: Humans; Mice; Animals; Mast Cells; Mucous Membrane; Transcriptome
PubMed: 37462672
DOI: 10.1084/jem.20230570 -
Nature Aug 2023In addition to its canonical function of protection from pathogens, the immune system can also alter behaviour. The scope and mechanisms of behavioural modifications by...
In addition to its canonical function of protection from pathogens, the immune system can also alter behaviour. The scope and mechanisms of behavioural modifications by the immune system are not yet well understood. Here, using mouse models of food allergy, we show that allergic sensitization drives antigen-specific avoidance behaviour. Allergen ingestion activates brain areas involved in the response to aversive stimuli, including the nucleus of tractus solitarius, parabrachial nucleus and central amygdala. Allergen avoidance requires immunoglobulin E (IgE) antibodies and mast cells but precedes the development of gut allergic inflammation. The ability of allergen-specific IgE and mast cells to promote avoidance requires cysteinyl leukotrienes and growth and differentiation factor 15. Finally, a comparison of C57BL/6 and BALB/c mouse strains revealed a strong effect of the genetic background on the avoidance behaviour. These findings thus point to antigen-specific behavioural modifications that probably evolved to promote niche selection to avoid unfavourable environments.
Topics: Animals; Mice; Allergens; Avoidance Learning; Central Amygdaloid Nucleus; Disease Models, Animal; Food Hypersensitivity; Immunoglobulin E; Intestines; Mast Cells; Mice, Inbred BALB C; Mice, Inbred C57BL; Parabrachial Nucleus; Solitary Nucleus
PubMed: 37437602
DOI: 10.1038/s41586-023-06362-4 -
Allergology International : Official... Jul 2023The signs and symptoms of chronic urticaria (CU) are caused by the activation and degranulation of skin mast cells (MCs). Recent studies have added to our understanding... (Review)
Review
The signs and symptoms of chronic urticaria (CU) are caused by the activation and degranulation of skin mast cells (MCs). Recent studies have added to our understanding of how and why skin MCs are involved and different in CU. Also, novel and relevant mechanisms of MC activation in CU have been identified and characterized. Finally, the use of MC-targeted and MC mediator-specific treatments has helped to better define the role of the skin environment, the contribution of specific MC mediators, and the relevance of MC crosstalk with other cells in the pathogenesis of CU. Here, we review these recent findings and their impact on our understanding of CU, with a focus on chronic spontaneous urticaria (CSU). Also, we highlight open questions, issues of controversy, and unmet needs, and we suggest what studies should be performed moving forward.
Topics: Humans; Urticaria; Mast Cells; Chronic Urticaria; Skin
PubMed: 37210251
DOI: 10.1016/j.alit.2023.05.003 -
The Journal of Allergy and Clinical... May 2024Chronic spontaneous urticaria (CSU) is an inflammatory skin disorder that manifests with itchy wheals, angioedema, or both for more than 6 weeks. Mast cells and... (Review)
Review
Chronic spontaneous urticaria (CSU) is an inflammatory skin disorder that manifests with itchy wheals, angioedema, or both for more than 6 weeks. Mast cells and basophils are the key pathogenic drivers of CSU; their activation results in histamine and cytokine release with subsequent dermal inflammation. Two overlapping mechanisms of mast cell and basophil activation have been proposed in CSU: type I autoimmunity, also called autoallergy, which is mediated via IgE against various autoallergens, and type IIb autoimmunity, which is mediated predominantly via IgG directed against the IgE receptor FcεRI or FcεRI-bound IgE. Both mechanisms involve cross-linking of FcεRI and activation of downstream signaling pathways, and they may co-occur in the same patient. In addition, B-cell receptor signaling has been postulated to play a key role in CSU by generating autoreactive B cells and autoantibody production. A cornerstone of FcεRI and B-cell receptor signaling is Bruton tyrosine kinase (BTK), making BTK inhibition a clear therapeutic target in CSU. The potential application of early-generation BTK inhibitors, including ibrutinib, in allergic and autoimmune diseases is limited owing to their unfavorable benefit-risk profile. However, novel BTK inhibitors with improved selectivity and safety profiles have been developed and are under clinical investigation in autoimmune diseases, including CSU. In phase 2 trials, the BTK inhibitors remibrutinib and fenebrutinib have demonstrated rapid and sustained improvements in CSU disease activity. With phase 3 studies of remibrutinib ongoing, it is hoped that BTK inhibitors will present an effective, well-tolerated option for patients with antihistamine-refractory CSU, a phenotype that presents a considerable clinical challenge.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Chronic Urticaria; Signal Transduction; Mast Cells; Animals; Receptors, IgE; Basophils; Protein Kinase Inhibitors
PubMed: 38141832
DOI: 10.1016/j.jaci.2023.12.008 -
Cancer Research Aug 2023Mast cells constitute indispensable immunoregulatory sentinel cells in the tumor microenvironment. A better understanding of the regulation and functions of mast cells...
UNLABELLED
Mast cells constitute indispensable immunoregulatory sentinel cells in the tumor microenvironment. A better understanding of the regulation and functions of mast cells in lung adenocarcinoma (LUAD) could uncover therapeutic approaches to reprogram the immunosuppressive tumor microenvironment. Here, we performed flow cytometry and single-cell RNA sequencing (scRNA-seq) of patient LUAD samples to comprehensively characterize LUAD-infiltrating mast cells. Mast cells exhibited functional heterogeneity and were enriched in LUAD with ground-glass opacity features (gLUAD). The mast cells in gLUAD exhibited proinflammatory and chemotactic properties while those in radiologically solid LUAD (sLUAD) were associated with tumor angiogenesis. Mast cells were an important source of CCL2 and correlated with the recruitment of CCR2+ CTL, a specific subcluster of preexhausted T cells with tissue-resident memory phenotype and enhanced cytotoxicity. Increased infiltration of mast cells and CCR2+ CTLs and their colocalization showed a strong association with favorable prognosis after surgery but were not associated with improved survival after chemotherapy. Collectively, these findings reveal a key role of mast cells in LUAD and their potential cross-talk with CTLs, suggesting that targeting mast cells may be an immunotherapeutic strategy for LUAD.
SIGNIFICANCE
Comprehensive characterization of mast cells in lung adenocarcinoma elucidates their heterogeneity and identifies interplay between mast cells and CCR2+ T cells that is associated with a favorable prognosis.
Topics: Humans; T-Lymphocytes, Cytotoxic; Mast Cells; Prognosis; Adenocarcinoma of Lung; Tumor Microenvironment; Lung Neoplasms; Receptors, CCR2
PubMed: 37249584
DOI: 10.1158/0008-5472.CAN-22-3140 -
International Journal of Molecular... Jun 2023Hematopoietic stem cells (HSCs) are defined based on their capacity to replenish themselves (self-renewal) and give rise to all mature hematopoietic cell types... (Review)
Review
Hematopoietic stem cells (HSCs) are defined based on their capacity to replenish themselves (self-renewal) and give rise to all mature hematopoietic cell types (multi-lineage differentiation) over their lifetime. HSCs are mainly distributed in the bone marrow during adult life, harboring HSC populations and a hierarchy of different kinds of cells contributing to the "niche" that supports HSC regulation, myelopoiesis, and lymphopoiesis. In addition, HSC-like progenitors, innate immune cell precursors such as macrophages, mast cells, natural killer cells, innate lymphoid cells, and megakaryocytes and erythrocyte progenitor cells are connected by a series of complex ontogenic relationships. The first source of mast cells is the extraembryonic yolk sac, on embryonic day 7. Mast cell progenitors circulate and enter peripheral tissues where they complete their differentiation. Embryonic mast cell populations are gradually replaced by definitive stem cell-derived progenitor cells. Thereafter, mast cells originate from the bone marrow, developing from the hematopoietic stem cells via multipotent progenitors, common myeloid progenitors, and granulocyte/monocyte progenitors. In this review article, we summarize the knowledge on mast cell sources, particularly focusing on the complex and multifaceted mechanisms intervening between the hematopoietic process and the development of mast cells.
Topics: Mast Cells; Immunity, Innate; Lymphocytes; Cell Differentiation; Hematopoiesis; Hematopoietic Stem Cells; Cell Lineage
PubMed: 37445862
DOI: 10.3390/ijms241310679