Mast Cell Signaling Research Articles

The receptor tyrosine kinase c-Kit controls IL-33 receptor signaling in mast cells

AbstractMembers of the Toll/interleukin-1 receptor (TIR) family are of importance for host defense and inflammation. Here we report that the TIR-family member interleukin-33R (IL-33R) cross-activates the receptor tyrosine kinase c-Kit in human and murine mast cells. The IL-33R–induced activation of signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase 1/2 (Erk1/2), protein kinase B (PKB), and Jun NH2-terminal kinase 1 (JNK1) depends on c-Kit and is required to elicit optimal effector functions. Costimulation with the c-Kit ligand stem cell factor (SCF) is necessary for IL-33–induced cytokine production in primary mast cells. The structural basis for this cross-activation is the complex formation between c-Kit, IL-33R, and IL-1R accessory protein (IL-1RAcP). We found that c-Kit and IL-1RAcP interact constitutively and that IL-33R joins this complex upon ligand binding. Our findings support a model in which signals from seemingly disparate receptors are integrated for full cellular responses.

The Limited Contribution of Fyn and Gab2 to the High Affinity IgE Receptor Signaling in Mast Cells

Several studies with mast cells from knock-out mice have suggested that the tyrosine kinase Fyn and its downstream substrate Gab2 may play a role in high affinity IgE receptor (FcepsilonRI)-mediated mast cell activation. To better understand the role of these two molecules and of Syk, we transiently transfected mast cells with small interference RNA (siRNA) targeted to Fyn, Gab2, or Syk to specifically decrease their expression. The siRNA suppression of Gab2 but not Fyn reduced activation of the phosphoinositide-3-kinase (PI3K) pathway as demonstrated by the change in phosphorylation of Akt; this indicates that Gab2 but not Fyn regulates this pathway. The decreased expression of Gab2 and Fyn had minor effects on degranulation. There were also some minor changes in activation of the NFAT or NFkappaB transcription factors in cells with reduced expression of Fyn or Gab2. Decreased Gab2 but not Fyn reduced the FcepsilonRI-induced activation of the Erk, Jnk, and p38 MAP kinases and the release of TNF-alpha. In contrast, decreased expression of Syk dramatically reduced FcepsilonRI-induced degranulation, activation of NFAT and NFkappaB. Therefore, the reduction in expression of these proteins in mast cells indicates that Syk is the major regulator of FcepsilonRI-mediated reactions, whereas Fyn has minor if any effects and Gab2 regulates primarily late events including MAP kinase activation and release of cytokines.

Functional Analysis of Lyn Kinase A and B Isoforms Reveals Redundant and Distinct Roles in FcεRI-Dependent Mast Cell Activation

Engagement of FcepsilonRI causes its phosphorylation by Lyn kinase. Two alternatively spliced variants, Lyn A and B, are expressed in mast cells, and both isoforms interact with FcepsilonRI. Unlike Lyn A, Lyn B lacks a 21-aa region in the N-terminal unique domain. In this study, we investigated the role of Lyn A and B isoforms in mast cell signaling and responses. Lyn B was found to be a poor inducer of mast cell degranulation and was less potent in both inositol 1,4,5-triphosphate production and calcium responses. Expression of Lyn B alone showed reduced phosphorylation of both phospholipase Cgamma-1 and -2 and decreased interaction of phospholipase Cgamma-1 with the phosphorylated linker for activation of T cells. Lyn B also showed increased binding of tyrosine-phosphorylated proteins, which included the negative regulatory lipid phosphatase SHIP-1. In contrast, both Lyn A and B caused similar total cellular tyrosine phosphorylation and FcepsilonRI phosphorylation and neither Lyn A nor Lyn B alone could completely restore mast cell degranulation or dampen the excessive cytokine production seen in the absence of Lyn. However, expression of both isoforms showed complementation and normalized responses. These findings demonstrate that Lyn B differs from Lyn A in its association with SHIP-1 and in the regulation of calcium responses. However, complementation of both isoforms is required in mast cell activation.

Synthesis and biological evaluation of novel (4 or 5-aryl)pyrazolyl-indoles as inhibitors of interleukin-2 inducible T-cell kinase (ITK)

Interleukin-2 inducible T-cell kinase (ITK) is one of five kinases that belong to the Tec kinase family that plays an important role in T-cell and mast cell signaling. Various reports point to a role of ITK in the treatment of allergic asthma. For example, it was shown that mice lacking ITK have reduced airway hyperresponsiveness, inflammation and tracheal responses in an allergic asthma model. In this article, we disclose novel ITK inhibitors based on (4 or 5-aryl)pyrazolyl-indole scaffold that were also found to be selective for ITK over other kinases like IRK, CDK2, GSK3ß and PKA.

Role of G-protein Coupled Receptor Kinases GRK2 and GRK3 in C3a Receptor Signaling in Human Mast Cells (133.12)

Abstract Studies with animal models have shown that complement components C3a and C5a play an important role in the effector phase of allergic asthma. We have previously shown that C3a activates human CD34+-derived mast cells to induce degranulation. To determine the role of GRKs on C3a receptor (C3aR) signaling in human mast cells, we used shRNA to knockdown GRK2 and GRK3 a human mast cell line, HMC-1 and CD34+-derived cultures of primary mast cells. We found that GRK2 and GKR3 knockdown inhibited C3aR desensitization as measured by enhanced C3a-induced Ca2+ mobilization in HMC-1 cells and greater degranulation in CD34+ mast cells but had no effect on receptor internalization. In addition, GRK3-knockdown in HMC-1 cells showed increased expression of cell surface C3aR and this was correlated with enhanced extracellular-signal-regulated kinase (ERK) activation and a four-fold increase in C3a-induced chemotaxis. Surprisingly, there was no enhancement of these responses in GRK2 knockdown mast cells. These findings suggest that while GRK2 and GRK3 are required for C3aR sensitization, presumably by promoting receptor phosphorylation, they play distinct roles in modulating downstream signaling such as ERK phosphorylation and chemotaxis.

The role of MyD88 in the synergy between FcϵR1, TLR4 and ST2 in mast cells. (91.5)

Abstract Mast cells are well established as important effector cells in allergic reactions. Cross-linking of the high affinity IgE receptor (FcϵRI) on mast cells by allergen causes degranulation leading to the release and generation of a variety of inflammatory mediators. IL-33 and lipopolysaccharide (LPS) are members of the IL-1 family that use MyD88 as an adaptor molecule for signalling. Alone, IL-33 and LPS are unable to cause mast cell degranulation but they can induce cytokine generation. In addition, IL-33 and LPS synergise with antigen/IgE for cytokine production in mast cells. IL-33 and LPS-induced cytokine production was abolished in MyD88-deficient (MyD88-/-) bone marrow-derived mast cells (BMMCs). Surprisingly, antigen/IgE-mediated cytokine production was also substantially reduced in MyD88-/- BMMCs. However, MyD88 had no effect on FcϵRI expression, calcium mobilisation or degranulation. The synergy between IL-33 and antigen/IgE in IL-13 production by BMMCs was shown to be MyD88-dependent. Similarly, MyD88 was required for cytokine production in LPS and antigen/IgE stimulated BMMCs. The synergy between LPS and antigen/IgE for cytokine generation also required p38 MAP kinase activation. These findings suggest that MyD88 signalling in mast cells could provide a novel target to modulate allergic diseases.

Absence of Tec family kinases Itk and Btk significantly impairs FcϵRI dependent mast cell responses (86.26)

Abstract While the etiology of asthma can be multi factorial, signaling through the IgE receptor (Fcϵ receptor I) on mast cells is critical to its onset. The Tec family tyrosine kinases ITK and BTK serve important roles as signal amplifiers downstream of the FcϵRI, however, their individual contribution to FcϵRI signaling has not been fully established. We have generated Itk and Btk double deficient (DKO) mice in an effort to determine the relative role of Itk and Btk to FcϵRI signaling in mast cells. Analyses of skin mast cells from these mice revealed reduced mast cell granule content and density. However, in vitro cultured bone marrow derived mast cells (BMMCs) had normal gross morphology and granule density. Mast cell histamine release was also compromised in DKO mice, likely associated with elevated endogenous IgE expression in these mice. In vitro growth analysis indicated that Btk negatively regulates BMMC growth as previously published, while the absence of both Itk/Btk did not further contribute to this phenotype. However, there was a significant reduction in FcϵRI mediated calcium responses, accompanied by reduced phosphorylation of PLCγ2 and the mitogen activated protein kinase p38. Lastly, a reduction in the production of several cytokines was also observed in DKO BMMCs. Our results suggest that Itk and Btk have redundant, complementary, and unique functions in mast cell FcϵRI signaling that could be pharmacologically manipulated to treat asthma.

Regulation of mast cell signaling by SHP-1 as a phosphatase and an adaptor (86.1)

Abstract To clarify how SHP-1 regulates mast cell signaling, we generated BMMC from motheaten (me), viable motheaten (mev), and control (WT) mice and examined signaling events and final outputs following FcϵRI and IL-3 stimulation. FcϵRI-induced tyrosine phosphorylation of SLP-76 and LAT, MAPK activation, and cytokine production were increased in me-/mev-BMMC. In addition, phosphorylation of SHP-1 was increased in mev. Since the activity of Lyn and Syk was comparable in all BMMC, these molecules are substrates of SHP-1. me-BMMC showed impaired PLCγ phosphorylation, calcium mobilization, and degranulation, which could not be observed in mev-BMMC. This result suggests that the expression of SHP-1 is sufficient for the positive regulation of these pathways. The absence of SHP-1 expression disrupted the association between SLP-76 and PLCγ. Next, we examined IL-3-dependent cell proliferation and cell death. When BMMC were stimulated with IL-3, ERK activation was increased and sustained in me-/mev. In accordance with increased ERK activation, apoptosis was decreased in me-/mev-BMMC. In contrast to the predicted role of ERK as a pro-survival molecule, IL-3-induced cell proliferation was much lower in me-/mev-BMMC than WT-BMMC. Addition of PD98059 resulted in the suppression of decreased apoptosis and cell proliferation in me-/mev-BMMC. These results suggest that SHP-1 positively regulates IL-3-dependent mast cell proliferation and apoptosis by inhibiting ERK activity.

TGFb1 Suppresses the Mast Cell Response In Vitro and In Vivo (86.6)

Abstract Mast cell activation is a critical component of allergic disease, and may be regulated by cytokines present in the microenvironment. We recently described the suppressive effects of TGFb1 on IgE signaling in mouse and human mast cells. We have furthered this study, demonstrating that TGF injection or aerosolization reduces mast cell IgE receptor expression in vivo, and suppresses eosinophil recruitment in a mast cell-dependent model of airway hyperresponsiveness. We find that TGFb1 inhibits expression of the key signaling molecules Syk, Fyn, Akt, and Stat5 at the protein level without any change in mRNA expression. In contrast, expression or activation of ERK, JNK, GSK, and p38 was unaffected. Fyn transfection partially reversed TGFb1-mediated suppression of IgE-induced IL-13 secretion. Our data support the theory that TGFb1 possesses potent mast cell suppressive activities both in vitro and in vivo.

Recycling endosomal membranes contribute to Toxoplasma gondii parasitophorous vacuole formation in mast cells (45.4)

Abstract For the obligate intracellular parasite, Toxoplasma gondii, elucidating its initial interactions with host cells and their parasitophorous vacuole membrane (PVM) is important for better understanding T. gondii infection. In many cell types, recycling endosomal (RE) trafficking often contributes to plasma membrane remodeling during processes such as phagocytosis. Previously, we characterized RE trafficking in RBL-2H3 mast cells and demonstrated IgE/antigen-stimulated outward trafficking of FITC-cholera toxin B (CTxB) bound to GM1 on RE membranes. When these cells are infected with virulent Type I strain tachyzoites, we find that invading parasites have an accumulation of FITC-CTxB on the PVM at early times after infection. This response is substantially enhanced when FITC-CTxB labels the RE pool in addition to the plasma membrane, providing evidence that RE membranes contribute to the nascent PVM. Consistent with earlier studies, IgE bound to its receptor at the plasma membrane shows no detectable accumulation at the PVM during this early stage (first hour) of infection. Under these conditions, antigen-stimulated degranulation is substantially inhibited, suggesting that parasitic infection interferes with normal signaling responses in these cells. Our ongoing research aims to further investigate the possible link between the PVM and RE trafficking and the potential immunomodulatory effects of T. gondii on infected mast cell signaling.

SHP2 protein-tyrosine phosphatase is a key regulator of mast cell signaling and development in mice (36.22)

Abstract SH2 domain-containing phosphatase-2 (SHP2; also called PTPN11) is a positive effector of growth signaling pathways downstream of receptor tyrosine kinases and immune receptors. The development of conditional knockout mouse models for SHP2 has resulted in a better understanding of the role of SHP2 in adult tissues and cell types. In bone marrow-derived mast cells, recent studies have implicated SHP2 in functioning as a positive effector of growth signaling via Kit receptor tyrosine kinase, and TNFα production via the high affinity IgE receptor. In this study, we describe the use of transgenic mice expressing Cre recombinase in connective tissue mast cells (CTMCs) to generate a selective SHP2 knockout in CTMCs (MC-SHP2 KO). Compared to control mice lacking Cre, MC-SHP2 KO mice display a drastic reduction in mast cells within the peritoneum and skin. Previous studies have demonstrated the critical importance of Kit Y567 and Y719 signaling to Src family kinases/Gab2 and phosphatidylinositol 3’ kinase (PI3K) pathways for development of peritoneal and skin mast cells in mice. Thus, our results suggest that SHP2 plays a key role in signaling via the Src/Gab2/PI3K axis downstream of Kit during mast cell development in mice. In vitro differentiation assays for CTMCs are being investigated to further explore the molecular mechanisms by which SHP2 regulates mast cell development.

Formation of a mast cell synapse: Fc epsilon RI membrane dynamics upon binding mobile or immobilized ligands on surfaces.

Fc epsilonRI on mast cells form a synapse when presented with mobile, bilayer-incorporated Ag. In this study, we show that receptor reorganization within the contacting mast cell membrane is markedly different upon binding of mobile and immobilized ligands. Rat basophilic leukemia mast cells primed with fluorescent anti-DNP IgE were engaged by surfaces presenting either bilayer-incorporated, monovalent DNP-lipid (mobile ligand), or chemically cross-linked, multivalent DNP (immobilized ligand). Total internal reflection fluorescence imaging and electron microscopy methods were used to visualize receptor reorganization at the contact site. The spatial relationships of Fc epsilonRI to other cellular components at the synapse, such as actin, cholesterol, and linker for activation of T cells, were also analyzed. Stimulation of mast cells with immobilized polyvalent ligand resulted in typical levels of degranulation. Remarkably, degranulation also followed interaction of mast cells, with bilayers presenting mobile, monovalent ligand. Receptors engaged with mobile ligand coalesce into large, cholesterol-rich clusters that occupy the central portion of the contacting membrane. These data indicate that Fc epsilonRI cross-linking is not an obligatory step in triggering mast cell signaling and suggest that dense populations of mobile receptors are capable of initiating low-level degranulation upon ligand recognition.

Insulin potentiates FcɛRI-mediated signaling in mouse bone marrow-derived mast cells

Factors contained in physiological microenvironments in tissues where mast cells differentiate and reside may influence mast cell responsiveness and modify antigen-dependent activation. A possible direct or indirect role of mast cell responses in diabetes mellitus prompted us to study the impact of insulin treatment on antigen triggered signaling pathways downstream of FcɛRI in bone marrow-derived mouse mast cells (BMMCs). We found that insulin alone stimulates tyrosine phosphorylation of tyrosine kinases Lyn, Syk, Fyn, the adapter protein Gab2 (Grb2-associated binding protein 2), Akt and activates ERK, JNK and p38 kinase. Effect of insulin on FcɛRI signaling pathways was marked by enhanced phosphorylation of Lyn, Fyn, Gab2 and Akt. Furthermore, BMMC stimulated with antigen in the presence of insulin responded with enhanced protein kinase θ (PKCθ) activity and increased JNK phosphorylation when compared to BMMC triggered with antigen alone. Functional studies reveal enhanced degranulation and altered cytoskeletal rearrangement when BMMCs were treated simultaneously with insulin and antigen. Our results suggest that insulin tunes antigen-mediated responses of mast cells.

Adapters in the organization of mast cell signaling

Mast cells are pivotal in innate immunity and play an important role in amplifying adaptive immunity. Nonetheless, they have long been known to be central to the initiation of allergic disorders. This results from the dysregulation of the immune response whereby normally innocuous substances are recognized as non-self, resulting in the production of IgE antibodies to these 'allergens'. Preformed and newly synthesized inflammatory (allergic) mediators are released from the mast cell following allergen-mediated aggregation of allergen-specific IgE bound to the high-affinity receptors for IgE (FcepsilonRI). Thus, the process by which the mast cell is able to interpret the engagement of FcepsilonRI into the molecular events necessary for release of their allergic mediators is of considerable therapeutic interest. Unraveling these molecular events has led to the discovery of a functional class of proteins that are essential in organizing activated signaling molecules and in coordinating and compartmentalizing their activity. These so-called 'adapters' bind multiple signaling proteins and localize them to specific cellular compartments, such as the plasma membrane. This organization is essential for normal mast cell responses. Here, we summarize the role of adapter proteins in mast cells focusing on the most recent advances toward understanding how these molecules work upon FcepsilonRI engagement.

Mechanisms of mast cell signaling in anaphylaxis

Mechanisms of mast cell signaling in anaphylaxis

CRAC channels and Ca2+ signaling in mast cells

Mast cells are integral members of the immune system. Upon activation by a rise in cytoplasmic Ca2+, they release a battery of paracrine signals, chemokines, and cytokines, which help sculpt the subsequent immune response. Ca2+ entry through store-operated Ca2+ release-activated Ca2+ (CRAC) channels in the plasma membrane is central for driving most of these responses. The molecular basis of the CRAC channel has been identified, with Orai1 forming the channel pore. Recent work has revealed that a range of mast cell responses are activated by spatially restricted Ca2+ signals just below the plasma membrane. These Ca2+ microdomains can activate cytosolic enzymes, leading to the generation of intracellular messengers as well as proinflammatory molecules like LTC4. In this review, we describe key features of CRAC channels in mast cells, how they generate local Ca2+ signals, and how the cell can decode these restricted signals to generate a raft of responses.

The β- and γ-isoforms of type I PIP5K regulate distinct stages of Ca2+ signaling in mast cells

Crosslinking of IgE receptors by antigen initiates Ca2+ mobilization in mast cells by activating phospholipase-C gamma-mediated hydrolysis of phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2]. The resulting inositol 1,4,5-trisphosphate-mediated Ca2+ release from the endoplasmic reticulum (ER) activates store-operated Ca2+ entry, which is necessary for exocytotic release of inflammatory mediators. To investigate roles for PtdIns(4,5)P2-synthesizing isozymes of the type I phosphatidylinositol 4-phosphate 5-kinase family (PIP5K-I) in mast cell signaling, we compared the ectopic expression of wild-type and catalytically inactive PIP5K-I beta in RBL-2H3 mast cells. Surprisingly, both antigen and thapsigargin-stimulated Ca2+ influx were reduced by overexpression of active PIP5K-I beta, whereas antigen-stimulated Ca2+ release from ER stores was unaffected. Consistent with these results, Ca2+ entry stimulated by antigen or thapsigargin was enhanced by expression of a plasma-membrane-associated inositol polyphosphate 5'-phosphatase, whereas antigen-stimulated Ca2+ release from stores was reduced. To investigate the role of PIP5K-I gamma in antigen-stimulated Ca2+ mobilization, we used bone-marrow-derived mast cells from PIP5K-I gamma(-/-) mice. Antigen-stimulated Ca2+ release from ER stores was substantially reduced in the absence of PIP5K-I gamma, but thapsigargin-mediated Ca2+ entry was unaffected. In summary, PIP5K-I gamma positively regulates antigen-stimulated Ca2+ release from ER stores, whereas PIP5K-I beta negatively regulates store-operated Ca2+ entry, suggesting that these different PIP5K-I isoforms synthesize functionally distinct pools of PtdIns(4,5)P2 at the plasma membrane.

Sphingosine Kinase1 Is Pivotal for FcεRI-Mediated Mast Cell Signaling and Functional Responses In Vitro and In Vivo

Mast cell degranulation is pivotal to allergic diseases; investigating novel pathways triggering mast cell degranulation would undoubtedly have important therapeutic potential. FcepsilonRI-mediated degranulation has contradictorily been shown to require SphK1 or SphK2, depending on the reports. We investigated the in vitro and in vivo specific role(s) of SphK1 and SphK2 in FcepsilonRI-mediated responses, using specific small interfering RNA-gene silencing. The small interfering RNA-knockdown of SphK1 in mast cells inhibited several signaling mechanisms and effector functions, triggered by FcepsilonRI stimulation including: Ca(2+) signals, NFkappaB activation, degranulation, cytokine/chemokine, and eicosanoid production, whereas silencing SphK2 had no effect at all. Moreover, silencing SPHK1 in vivo, in different strains of mice, strongly inhibited mast cell-mediated anaphylaxis, including inhibition of vascular permeability, tissue mast cell degranulation, changes in temperature, and serum histamine and cytokine levels, whereas silencing SPHK2 had no effect and the mice developed anaphylaxis. Our data differ from a recent report using SPHK1(-/-) and SPHK2(-/-) mice, which showed that SphK2 was required for FcepsilonRI-mediated mast cell responses. We performed experiments in mast cells derived from SPHK1(-/-) and SPHK2(-/-) mice and show that the calcium response and degranulation, triggered by FcepsilonRI-cross-linking, is not different from that triggered in wild-type cells. Moreover, IgE-mediated anaphylaxis in the knockout mice showed similar levels in temperature changes and serum histamine to that from wild-type mice, indicating that there was no protection from anaphylaxis for either knockout mice. Thus, our data strongly suggest a previously unrecognized compensatory mechanism in the knockout mice, and establishes a role for SphK1 in IgE-mediated mast cell responses.

PI3Kγ Differentially Regulates FcεRI-Mediated Degranulation and Migration of Mast Cells by and toward Antigen

Phosphatidylinositol 3-kinase (PI3K) has been recognized as an important downstream effector of high-affinity receptor for IgE (FcεRI) signaling in mast cells, but little is known about the isoform specificity of PI3Ks on the FcεRI-mediated migration toward the antigen (Ag). In the present study, we explored the role of PI3Kγ on mast cell migration. The treatment of bone marrow-derived mast cells (BMMCs) with a PI3Kγ inhibitor, AS605240, significantly repressed FcεRI-induced degranulation and migration. The culture supernatants of wild-type mast cells stimulated with IgE and Ag attracted FcεRIβ^–/– mast cells which did not express FcεRI on their cell surface, indicating that the migration appears to be dependent on an autocrine/paracrine secretion of soluble factors from the mast cells. Adenosine, which is produced by mast cells, showed a strong activity to attract mast cells. Pertussis toxin (PTX) significantly inhibited the migration toward both the supernatant and adenosine. The supernatant from mast cells pretreated with wortmannin (Wort) and stimulated with IgE and Ag still exhibited the activity as chemoattractant, while the BMMCs pretreated with Wort did not migrate toward the supernatant. Although PTX significantly reduced the activation of AKT/PKB and migration, PTX had no effects on degranulation. These results suggest that PI3Kγ activation through PTX-sensitive G-protein-coupled receptor as a secondary response of FcεRI cross-linking regulates FcεRI-mediated mast cell migration toward the Ag, while simultaneously activated PI3Kγ through a PTX-insensitive pathway might have an effect on degranulation.

New Insights on the Possible Role of Mast Cells in Aspirin-Induced Asthma

Nonsteroidal anti-inflammatory drugs (NSAIDs) are major drugs used in the treatment of inflammation and pain in a wide variety of disorders. The best-known mechanism of action of NSAIDs is the inhibition of prostaglandin synthesis as a result of their action on cyclooxygenase (COX) enzymes. However, data have been accumulating through the years indicating that NSAIDs also act on other targets in cell signaling. It has been established that NSAIDs induce anti-inflammatory effects independent of COX. Acetylsalicylic acid (ASA) and other inhibitors of COX induce severe bronchospasms and asthmatic attacks in a significant population of asthmatic patients. The etiology of ASA induced asthma is complex and not fully understood, but most evidence points towards an abnormality of arachidonic acid (AA) metabolism. Since doses of ASA necessary to treat chronic inflammatory diseases appeared much higher than those required to inhibit PG synthesis, COX-independent mechanisms of NSAIDs were postulated. Recently, we have shown that NSAIDs induced expression of heat shock proteins specially HSP70. Heat shock proteins (HSPs) are normal intracellular proteins that are produced in greater amounts when cells are subjected to stress or injury. Interestingly, a potential pathogenic role for heat shock proteins in diseases such as autoimmune disease, vascular disease has been reported. Because mast cells have been reported to play a role in the pathogenesis of ASA induced asthma, a link between heat shock proteins and this disease could postulated. In this review, an overview is given on aspirin-induced asthma and the cells and mediators that may play a role therein. Mast cell signaling with regard to interaction with NSAIDs and heat shock proteins (HSPs) and toll-like receptors (TLRs) is further highlighted.