IL‐33 causes selective mast cell tolerance to bacterial cell wall products by inducing IRAK1 degradation

Abstract

Mast cells are important cellular constituents of epithelial-mesenchymal interactions, densely located at sites of microbial entry into the host where they are continuously exposed to products from commensals. In order to avoid excessive activation and the associated pathology, mast cell responses to TLR agonists must be tightly regulated. Here, we show that exposure in vitro to subactivating levels of the epithelial cell product, IL-33, renders mast cells insensitive to bacterial cell wall products. Mast cell responsiveness to Ag, cytoplasmic dsDNA, and TLR7/8 agonists is unaffected or enhanced by IL-33. The IL-33-induced mast cell selective tolerance requires the IL-33 receptor ST2 and peritoneal mast cells from St2 −/− mice display a constitutively activated phenotype, demonstrated by increased expression of activation markers including CD11b and CD28. IL-33 exposure neither affects the levels of TLR4, MyD88, TIRAP, IL-1R associated kinase 2 (IRAK2), or IRAK4, nor induces persistent A20 or Tollip expression, but potently causes ST2-dependent IRAK1 degradation. We show that while IRAK2 is redundant for TLR4 signaling, IRAK1 is essential for TLR4 signaling in mast cells. We suggest that IL-33 produced during homeostasis retains mast cells in an unresponsive state to bacterial cell wall products via IRAK1 degradation, thus preventing chronic inflammation and tissue destruction.Keywords: IL-33 r IRAK1 r Mast cells r ST2 r TLRs Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMast cells are closely associated with the epithelium [1], contributing to barrier function [2]. Therefore, responses to commensal bacteria must be tightly regulated to prevent the pathology Correspondence: Prof. Silvia Bulfone-Paus e-mail: Silvia.bulfone-paus@manchester.ac.uk associated with unnecessary immune activation. The crucial role of the tissues in regulating immunity is increasingly being recognized [3] and we hypothesized that epithelial or endothelial cell products may orchestrate this regulation.IL-33 and its receptor ST2 have complex roles in the LPS response [4][5][6][7][8]. IL-33 is expressed constitutively by epithelial cells [9,10] and its expression is upregulated during inflammation [11]. Mast cells express ST2 and are activated by IL-33 to release cytokines and chemokines [12][13][14][15] and, furthermore, the fact that LPS and IL-33 share the TLR/IL1R signaling pathway C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 980Hilary Sandig et al. Eur. J. Immunol. 2013. 43: 979-988 raises the possibility that cross-talk or cross-tolerance could occur between them. While the role of IL-33 during inflammation has been widely investigated, little is known about the function of constitutively expressed IL-33. Typically, TLR4 signaling proceeds via MyD88-dependent and independent pathways but in mast cells TLR4 ligation does not engage the MyD88-independent pathway [16]. The molecular details of the MyD88-dependent pathway in mast cel...

Endotoxin tolerance in mast cells, its consequences for IgE-mediated signalling, and the effects of BCL3 deficiency

“…Moreover, various types and sources of LPS are used by different laboratories. We aimed to connect our study to previous studies 7, 17, 18 and thus, we first verified that the BMMCs in use can become tolerant in response to an initial stimulation with LPS (R595 from Salmonella minnesota ). BMMCs were left untreated (“naive”) or pretreated with LPS (300 ng/ml) for 24 h (“tolerant”).…”

“…To avoid exaggerated proinflammatory activation of MCs by microbial constituents, such as LPS and lipopeptides, acquiring a state of tolerance should be beneficial. It has been demonstrated previously using BMMCs and a MC line that MCs can undergo ET 7, 17, 18 . Moreover, isolated human gut MCs express TLR4, but did not respond to LPS indicating tolerance 35 .…”

“…Using BMMCs, it has been demonstrated that MCs can undergo ET 7, 17, 18 . Differentiation of BMMCs is a time-consuming process and their phenotype is known to be sensitive to the differentiation conditions used, such as the type of FCS and the source and composition of cytokines.…”

“…upregulation of the deubiquitinase A20 or degradation of IRAK1 18, 39, 40 ), which could also be a reason for loss of NFκB binding in tolerant cells. Indeed, early phosphorylation and degradation of IκBα was suppressed in tolerant BMMCs.…”

Mast hücreleri ve aktivasyonu

“…Enfeksiyöz ajanlarla temas sonrası mast hücre aktivasyonu TLR aracılığıyla oluşur. Mast hücreleri üzerindeki TLR1,2,5,9 Gram (+) bakteriler ve mikoplazma, TLR3,7,8 virüsler, TLR4 ise Gram (-) bakteriler için fizyolojik ligand görevi görmektedir 21 . Bir çalışmada atopik dermatitte ekzemanın Staphylococcus aureus ile şiddetlenmesi mast hücrelerinin TLR ile aktivasyonuna bağlanmıştır 22 .…”