Anaphylactic shock is characterized by elevated immunoglobulin-E (IgE) antibodies that signal via the high affinity Fcε receptor (FcεRI) to release inflammatory mediators. Here we report that the novel cytokine interleukin-33 (IL-33) potently induces anaphylactic shock in mice and is associated with the symptom in humans. IL-33 is a new member of the IL-1 family and the ligand for the orphan receptor ST2. In humans, the levels of IL-33 are substantially elevated in the blood of atopic patients during anaphylactic shock, and in inflamed skin tissue of atopic dermatitis patients. In murine experimental atopic models, IL-33 induced antigen-independent passive cutaneous and systemic anaphylaxis, in a T cell–independent, mast cell–dependent manner. In vitro , IL-33 directly induced degranulation, strong eicosanoid and cytokine production in IgE-sensitized mast cells. The molecular mechanisms triggering these responses include the activation of phospholipase D1 and sphingosine kinase1 to mediate calcium mobilization, Nuclear factor–κB activation, cytokine and eicosanoid secretion, and degranulation. This report therefore reveals a hitherto unrecognized pathophysiological role of IL-33 and suggests that IL-33 may be a potential therapeutic target for anaphylaxis, a disease of considerable unmet medical need.

Atopic allergy is characterized by an increase in IgE antibodies that signal through the high-affinity Fcepsilon receptor (FcepsilonRI) to induce the release of inflammatory mediators from mast cells. For unknown reasons, the prevalence of allergic diseases has recently increased steeply in the developed world. However, this increase has not been mirrored in developing countries, even though IgE concentrations are often greatly elevated in individuals from these countries, owing to nonspecific IgE induction by universally present parasitic worms. Here we offer one explanation for this paradox based on the properties of ES-62, a molecule secreted by filarial nematodes. We found that highly purified, endotoxin-free ES-62 directly inhibits the FcepsilonRI-induced release of allergy mediators from human mast cells by selectively blocking key signal transduction events, including phospholipase D-coupled, sphingosine kinase-mediated calcium mobilization and nuclear factor-kappaB activation. ES-62 mediates these effects by forming a complex with Toll-like receptor 4, which results in the sequestration of protein kinase C-alpha (PKC-alpha). This causes caveolae/lipid raft-mediated, proteasome-independent degradation of PKC-alpha, a molecule important for the coupling of FcepsilonRI to phospholipase D and mast cell activation. We also show that ES-62 is able to protect mice from mast cell-dependent hypersensitivity in the skin and lungs, indicating that it has potential as a novel therapeutic for allergy.

Rheumatoid arthritis pathogenesis comprises dysregulation in both innate and adaptive immunity. There is therefore intense interest in the factors that integrate these immunologic pathways in rheumatoid arthritis. In this paper, we report that IL-33, a novel member of the IL-1 family, can exacerbate anti–glucose-6-phosphate isomerase autoantibody-induced arthritis (AIA). Mice lacking ST2 (ST2−/−), the IL-33 receptor α-chain, developed attenuated AIA and reduced expression of articular proinflammatory cytokines. Conversely, treatment of wild-type mice with rIL-33 significantly exacerbated AIA and markedly enhanced proinflammatory cytokine production. However, IL-33 failed to increase the severity of the disease in mast cell-deficient or ST2−/− mice. Furthermore, mast cells from wild-type, but not ST2−/−, mice restored the ability of ST2−/− recipients to mount an IL-33–mediated exacerbation of AIA. IL-33 also enhanced autoantibody-mediated mast cell degranulation in vitro and in synovial tissue in vivo. Together these results demonstrate that IL-33 can enhance autoantibody-mediated articular inflammation via promoting mast cell degranulation and proinflammatory cytokine production. Because IL-33 is derived predominantly from synovial fibroblasts, this finding provides a novel mechanism whereby a host tissue-derived cytokine can regulate effector adaptive immune response via enhancing innate cellular activation in inflammatory arthritis.

ES-62, an immunomodulator secreted by filarial nematodes, exhibits therapeutic potential in mouse models of allergic inflammation, at least in part by inducing the desensitisation of FcεRI-mediated mast cell responses. However, in addition to their pathogenic roles in allergic and autoimmune diseases, mast cells are important in fighting infection, wound healing, and resolving inflammation, reflecting that mast cells exhibit a phenotypic and functional plasticity. We have therefore characterised the differential functional responses to antigen (via FcεRI) and LPS and their modulation by ES-62 of the mature peritoneal-derived mast cells (PDMC; serosal) and those of the connective tissue-like mast cells (CTMC) and the mucosal-like mast cells derived from bone marrow progenitors (BMMC) as a first step to produce disease tissue-targeted therapeutics based on ES-62 action. All three mast cell populations were rendered hyporesponsive by ES-62 and whilst the mechanisms underlying such desensitisation have not been fully delineated, they reflect a downregulation of calcium and PKCα signalling. ES-62 also downregulated MyD88 and PKCδ in mucosal-type BMMC but not PDMC, the additional signals targeted in mucosal-type BMMC likely reflecting that these cells respond to antigen and LPS by degranulation and cytokine secretion whereas PDMC predominantly respond in a degranulation-based manner.

IntroductionFragment crystallizable receptors (FcRs) are receptors on immune cells that bind to the Fc region of immunoglobulins. Fc␥Rs that bind to the most common type of immunoglobulin (IgG), are expressed on the surface of many different immune cell types including monocytes, macrophages, dendritic cells, and neutrophils. [1][2][3] In humans, 3 different classes of activatory IgG receptors have been defined: Fc␥RI (CD64), Fc␥RIIa (CD32a), and Fc␥RIII (CD16), each of which has a variety of isoforms with differing affinities for IgG, tissue distribution, and level of expression. [1][2][3][4][5][6] The high affinity IgG receptor, Fc␥RI, is a 72-kD type-I membrane glycoprotein constitutively expressed on monocyte and macrophage lineage cells. 4 Fc␥RI is a member of the multichain immune recognition receptor family, comprising hetero-oligomeric complexes of a ligand-binding ␣-chain and a signaling ␥-chain usually found in association with other immune receptors. [1][2][3][4][5][6] The ␥-chain contains a signaling motif termed the "immunoreceptor tyrosinebased activation motif" (ITAM): it is through the ITAM-bearing chain that most FcRs trigger intracellular signal transduction cascades. The low-affinity receptor, Fc␥RIIa, is the most broadly distributed human Fc␥R and is expressed on many cell types, such as monocytes, neutrophils, and platelets. 1,7 This low-affinity receptor preferentially binds complexes of IgG and is the only Fc receptor that contains an ITAM of its own. Thus, it is the only Fc receptor that does not need to oligomerize with a ␥-chain in order to signal. 4,8,9 There is no identified murine equivalent of Fc␥RIIa. 1 On myeloid cells, aggregation of Fc␥Rs during the early stages of infection leads to several cellular responses, including the internalization of immune complexes by endocytosis or opsonized particles through phagocytosis, degranulation with the release of proteases, activation of respiratory burst, and secretion of cytokines. 5,[10][11][12] The presentation of antigens derived from internalized complexes forms an important component of our adaptive immune response, and dysregulation of this pathway is reported to be linked to increased susceptibility to bacterial sepsis. 13 The safe clearance of immune complexes toward the latter stages of infection is also dependent on FcR expressing mononuclear phagocytes. Dysfunction in the clearance of immune complexes is reported to be associated with immunopathology, autoimmunity, and allergic disease. 9,14 This represents one of the critical but poorly understood functions of Fc receptors, ie, the determination of the antigenic fate of immune complexes; specifically, whether to internalize and digest them in a way that is noninflammatory or to reinforce antigen presentation combined with immune activation and associated proinflammatory signaling.Studies on differential functions mediated by individual Fc receptors in immune activation/homeostasis are complicated by the coexistence of several FcRs on phagocytic cells-it is difficult to identi...