IgE and IL‐33−mediated triggering of human basophils inhibits TLR4−induced monocyte activation

Abstract

Basophils are circulating granulocytes, best known as effector cells in allergic reactions.Recent studies in mice suggest that they might also participate in the suppression of chronic inflammation. The aim of this study was to assess the ability of purified human basophils to modulate monocyte responses upon IL-33 and IgE triggering. Activation of human basophils with IL-33 induced the production of IL-4 and the release of histamine, and enhanced their IgE-mediated activation. In addition, basophils triggered with IL-33 and anti-IgE significantly suppressed the LPS-induced production of the proinflammatory cytokine TNF-α and the upregulation of the costimulatory molecule CD80 by monocytes. These effects were mainly explained by the release of histamine, as they could be inhibited by the histamine receptor 2 antagonist ranitidine, with a smaller contribution of IL-4. In contrast, basophil-derived IL-4 and histamine had opposing effects on the expression of the inhibitory Fc γ receptor IIb and the production of IL-10 by monocytes. Our data show that basophils can influence monocyte activation and suggest a previously unrecognized role for human basophils in the modulation of monocyte-mediated immune responses, through the balanced secretion of histamine and IL-4.Keywords: Basophils r Cellular activation r Histamine r Immune regulation r Monocytes Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionBasophils are circulating granulocytes, representing less than 1% of peripheral blood leukocytes. They are classically known for their involvement as effector cells in allergic reactions [1][2][3]. Because of their paucity and the difficulty in isolating them, there is still relatively little information available on their functions and potential immunomodulatory effects [4]. Studies in mice suggest a possible role for basophils in the induction of adaptive immunity in the context of Th2 responses, where they have been shown to be the major producers of , although their function as Correspondence: Dr. Felice Rivellese e-mail: rivelles@gmail.com antigen presenting cells and their dispensability in the induction of Th2 responses are still under debate [6,7]. In addition, recent experimental data showed how these rare leukocytes might also exert anti-inflammatory effects in the context of autoimmune and allergic inflammation. In a mouse model of arthritis, basophils have been implicated in the immunosuppressive response mounted upon injection of intravenous immunoglobulin (IVIG) [8]. Briefly, the authors proposed the following scenario to elucidate IVIG-mediated immune suppression: myeloid-derived cells, in response to the sialylated fraction of IVIG, release IL-33, which, in turn, activates basophils to produce IL-4. Finally, basophil-derived IL-4 induces the upregulation of the inhibitory Fc γ Receptor (FcγRIIb) on inflammatory macrophages, leading to the suppression of antibody-dependent inflammation. Thus, IL-33www.eji-journal.eu 3046 Felice R...

Ability of Interleukin‐33– and Immune Complex–Triggered Activation of Human Mast Cells to Down‐Regulate Monocyte‐Mediated Immune Responses

“…In vivo, IL-33 has been implicated in the ability of mast cells to contribute to the development of arthritis in murine experimental models (23,24), and high levels of IL-33 have been found in the serum and synovial fluid of patients with RA and those with other inflammatory arthritides (25). In addition to these proinflammatory properties, which are consistent with the described role of IL-33 as an alarmin, recent evidence suggests that this cytokine can also mediate immunoregulatory responses in various settings, by, for example, promoting regulatory T and B cell activity and suppressing monocyte activation through its effects on basophils (26)(27)(28)(29)(30)(31). Thus, similar to the findings regarding mast cells, the specific functions of IL-33 in the pathogenesis of autoimmune diseases, including arthritis, are still unclear (32,33).…”

“…For blocking experiments, supernatants of activated mast cells were preincubated with anti–IL‐10 antibody or rat IgG2a as a matched isotype control (BD Biosciences), at 10 μg/ml for 30 minutes at 37°C in an atmosphere of 5% CO 2 , prior to being incubated with the monocytes. For inhibition of histamine, monocytes were preincubated for 30 minutes at 37°C with the histamine receptor 2 antagonist ranitidine (Sigma) at 10 −4 M .…”

Mast cells in rheumatic disease

“…These studies have shown increased degranulation and cytokine production when mast cells are exposed to combined triggers of e.g. IL-3, IL-4 and IL-33 with FcεRI crosslinking (Gebhardt et al, 2002;Lorentz et al, 2005;Ochi et al, 2000;Rivellese et al, 2014). Whereas these studies are important for understanding of the role of cytokines in allergic responses, Fcγ receptors, as compared to FcεRI, are probably more important for mast cell activation in rheumatoid arthritis.…”

Are Basophils and Mast Cells Masters in HIV Infection?

“…Although the physiological role of mast cells and basophils remains enigmatic, there is now increasing evidence that these cells are critically involved not only in allergic disorders but also in autoimmune and infectious diseases, immunodeficiencies, and cancer [13,14,15,17,83], with multifaceted roles due to their ability to mediate both pro- and anti-inflammatory/immunomodulatory responses [21,23,84]. …”

“…However, there is now evidence that mast cells and basophils are versatile effector and regulatory cells able to initiate and modulate both innate and adaptive immune responses to parasites and bacterial pathogens [12,19,20]. Similarly, basophils and mast cells have been involved in many physiological and pathological processes, such as autoimmunity [21,22] and cancer [10], where they can play multifaceted roles with both pro- and anti-inflammatory/immunomodulatory functions [21,23]. The role of basophils and mast cells in viral infections is more enigmatic and has been less well studied [13].…”