Signal Transduction Pathways Activated by Innate Immunity in Mast Cells: Translating Sensing of Changes into Specific Responses

Espinosa-Riquer, Zyanya P; Segura-Villalobos, Deisy; Ramírez-Moreno, Itzel G; Pérez-Rodríguez, Marian Jesabel; Lamas, Marta; González-Espinosa, Claudia

doi:10.3390/cells9112411

Cited by 39 publications

(34 citation statements)

References 240 publications

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“…As components of innate immunity as well as bridges between innate and adaptive immune functions, MCs are ideally localized in tissues to act as sentinels that organize antimicrobial and anti-parasitic defenses [ 74 , 75 ]. On the other hand, MCs can also trigger hypersensitivity reactions upon exposure to exogenous antigens, drugs, venoms, or endogenous alarmins released by damaged or inflamed tissues.…”

Section: Discussionmentioning

confidence: 99%

“…In response to ligand binding, the ST2/IL-1RacP complex will initiate a sequence of phosphorylation and ubiquitination events starting with the recruitment of the adapter MyD88 (myeloid differentiation primary response gene 88) through its TIR domain (toll/interleukin-1 receptor), followed by members of the IRAK family (interleukin-1 receptor–associated kinase), the E3 ubiquitin ligase TRAF6 (TNF receptor-associated factor 6), and eventually TAK1 (TGF-β-activated kinase 1) [ 68 , 74 , 82 , 83 ]. TAK1 is the starting point of several cascades, among which are the stress-associated kinases p38 and JNK as well as NF-κB.…”

Section: Discussionmentioning

confidence: 99%

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Cytokines Stimulated by IL-33 in Human Skin Mast Cells: Involvement of NF-κB and p38 at Distinct Levels and Potent Co-Operation with FcεRI and MRGPRX2

Franke

Wang

Zuberbier

et al. 2021

IJMS

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The IL-1 family cytokine IL-33 activates and re-shapes mast cells (MCs), but whether and by what mechanisms it elicits cytokines in MCs from human skin remains poorly understood. The current study found that IL-33 activates CCL1, CCL2, IL-5, IL-8, IL-13, and TNF-α, while IL-1β, IL-6, IL-31, and VEGFA remain unaffected in cutaneous MCs, highlighting that each MC subset responds to IL-33 with a unique cytokine profile. Mechanistically, IL-33 induced the rapid (1–2 min) and durable (2 h) phosphorylation of p38, whereas the phosphorylation of JNK was weaker and more transient. Moreover, the NF-κB pathway was potently activated, as revealed by IκB degradation, increased nuclear abundance of p50/p65, and vigorous phosphorylation of p65. The activation of NF-κB occurred independently of p38 or JNK. The induced transcription of the cytokines selected for further study (CCL1, CCL2, IL-8, TNF-α) was abolished by interference with NF-κB, while p38/JNK had only some cytokine-selective effects. Surprisingly, at the level of the secreted protein products, p38 was nearly as effective as NF-κB for all entities, suggesting post-transcriptional involvement. IL-33 did not only instruct skin MCs to produce selected cytokines, but it also efficiently co-operated with the allergic and pseudo-allergic/neurogenic activation networks in the production of IL-8, TNF-α, CCL1, and CCL2. Synergism was more pronounced at the protein than at the mRNA level and appeared stronger for MRGPRX2 ligands than for FcεRI. Our results underscore the pro-inflammatory nature of an acute IL-33 stimulus and imply that especially in combination with allergens or MRGPRX2 agonists, IL-33 will efficiently amplify skin inflammation and thereby aggravate inflammatory dermatoses.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cytokines Stimulated by IL-33 in Human Skin Mast Cells: Involvement of NF-κB and p38 at Distinct Levels and Potent Co-Operation with FcεRI and MRGPRX2

Franke

Wang

Zuberbier

et al. 2021

IJMS

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“…Agonists encompass not only multiple cationic drugs, but also antimicrobial and neuropeptides like Substance P (SP), making it a universally operating receptor of MCTC-type MCs [ 4 , 6 ]. MRGPRX2’s importance as a central signaling unit of this MC type has been widely recognized by the MC community [ 10 , 11 , 12 , 13 , 16 , 65 , 66 , 67 ]. As research into MRGPRX2 began only recently, less is known about its modulation by autocrine and paracrine factors compared to FcεRI.…”

Section: Discussionmentioning

confidence: 99%

Thymic Stromal Lymphopoietin Promotes MRGPRX2-Triggered Degranulation of Skin Mast Cells in a STAT5-Dependent Manner with Further Support from JNK

Babina

Wang

Franke

et al. 2021

Cells

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Thymic stromal lymphopoietin (TSLP) is released by epithelial cells following disturbed homeostasis to act as “alarmin” and driver of Th2-immunity. Aberrant TSLP expression is a hallmark of atopic diseases, including atopic dermatitis (AD). Mast cells (MCs) are overabundant in AD lesions and show signs of degranulation, but it remains unknown whether TSLP contributes to granule discharge. Degranulation of skin MCs proceeds via two major routes, i.e., FcεRI-dependent (allergic) and MRGPRX2-mediated (pseudo-allergic/neurogenic). Evidence is accumulating that MRGPRX2 may be crucial in the context of skin diseases, including eczema. The current study reveals TSLP as a novel priming factor of human skin MCs. Interestingly, TSLP selectively cooperates with MRGPRX2 to support granule discharge, while it does not impact spontaneous or FcεRI-driven exocytosis. TSLP-assisted histamine liberation triggered by compound 48/80 or Substance P, two canonical MRGPRX2 agonists, was accompanied by an increase in CD107a+ cells (a MC activation marker). The latter process was less potent, however, and detectable only at the later of two time points, suggesting TSLP may prolong opening of the granules. Mechanistically, TSLP elicited phosphorylation of STAT5 and JNK in skin MCs and the reinforced degranulation critically depended on STAT5 activity, while JNK had a contributory role. Results from pharmacological inhibition were confirmed by RNA-interference, whereby silencing of STAT5 completely abolished the priming effect of TSLP on MRGPRX2-mediated degranulation. Collectively, TSLP is the first factor to favor MRGPRX2- over FcεRI-triggered MC activation. The relevance of TSLP, MCs and MRGPRX2 to pruritis and atopic skin pathology indicates broad repercussions of the identified connection.

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“…Mast cells are able to recognize many different PAMPs, mainly through the use of cell surface pattern recognition receptors (PRRS) such as TLRs [ 20 , 21 ]. What TLRs are actually expressed on mature mast cells is currently a matter of debate, with different studies showing conflicting results [ 41 ]. Surprisingly, a proteome study on human and mouse primary mast cells found an absence of many innate immune sensors, including all TLRs [ 42 ].…”

Section: Innate Immunitymentioning

confidence: 99%

“…Despite this, TLR agonists can cause changes in gene expression, release of inflammatory mediators and mast cell migration in several models [ 43 ]. While some studies show otherwise, TLR activation is generally not thought to lead to rapid degranulation as seen with activation of FcεRI [ 41 , 43 ]. Mast cells can also utilize Dectin-1 to sense β-glucans from fungi [ 44 ] and the intracellular receptors RIG-I, MDA5 and TLR3 to detect viruses [ 45 , 46 , 47 ].…”

Section: Innate Immunitymentioning

confidence: 99%

Harnessing the Power of Mast Cells in unconventional Immunotherapy Strategies and Vaccine Adjuvants

Willows

Kulka

2020

Cells

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Mast cells are long-lived, granular, myeloid-derived leukocytes that have significant protective and repair functions in tissues. Mast cells sense disruptions in the local microenvironment and are first responders to physical, chemical and biological insults. When activated, mast cells release growth factors, proteases, chemotactic proteins and cytokines thereby mobilizing and amplifying the reactions of the innate and adaptive immune system. Mast cells are therefore significant regulators of homeostatic functions and may be essential in microenvironmental changes during pathogen invasion and disease. During infection by helminths, bacteria and viruses, mast cells release antimicrobial factors to facilitate pathogen expulsion and eradication. Mast cell-derived proteases and growth factors protect tissues from insect/snake bites and exposure to ultraviolet radiation. Finally, mast cells release mediators that promote wound healing in the inflammatory, proliferative and remodelling stages. Since mast cells have such a powerful repertoire of functions, targeting mast cells may be an effective new strategy for immunotherapy of disease and design of novel vaccine adjuvants. In this review, we will examine how certain strategies that specifically target and activate mast cells can be used to treat and resolve infections, augment vaccines and heal wounds. Although these strategies may be protective in certain circumstances, mast cells activation may be deleterious if not carefully controlled and any therapeutic strategy using mast cell activators must be carefully explored.

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Signal Transduction Pathways Activated by Innate Immunity in Mast Cells: Translating Sensing of Changes into Specific Responses

Cited by 39 publications

References 240 publications

Cytokines Stimulated by IL-33 in Human Skin Mast Cells: Involvement of NF-κB and p38 at Distinct Levels and Potent Co-Operation with FcεRI and MRGPRX2

Cytokines Stimulated by IL-33 in Human Skin Mast Cells: Involvement of NF-κB and p38 at Distinct Levels and Potent Co-Operation with FcεRI and MRGPRX2

Thymic Stromal Lymphopoietin Promotes MRGPRX2-Triggered Degranulation of Skin Mast Cells in a STAT5-Dependent Manner with Further Support from JNK

Harnessing the Power of Mast Cells in unconventional Immunotherapy Strategies and Vaccine Adjuvants

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