The IL-3/IL-5/GM-CSF Common β Receptor Plays a Pivotal Role in the Regulation of Th2 Immunity and Allergic Airway Inflammation

Dai

J. Zhejiang Univ. Sci. B

et al. 2015

Abstract:Objective: Airway inflammation and airway hyper-responsiveness (AHR) are principle pathological manifestations of asthma. Cluster of differentiation 69 (CD69) is a well-known co-stimulatory factor associated with the activation, proliferation as well as apoptosis of immune cells. This study aims to examine the effect of anti-CD69 monoclonal antibody (mAb) on the pathophysiology of a mouse model of asthma. Methods: A murine model of ovalbumin (OVA)-induced allergic airway inflammation was used in this study. Briefly, mice were injected with 20 μg chicken OVA intraperitoneally on Days 0 and 14, followed by aerosol provocation with 1% (0.01 g/ml) OVA on Days 24, 25, and 26. Anti-CD69 mAb or isotype IgG was injected intraperitoneally after OVA challenge; dexamethasone (DXM) was administrated either before or after OVA challenge. AHR, mucus production, and eosinophil infiltration in the peribronchial area were examined. The levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-5 (IL-5) in bronchoalveolar lavage fluid (BALF) were also assayed as indices of airway inflammation on Day 28 following OVA injection. Results: Pretreatment with DXM together with anti-CD69 mAb treatment after OVA provocation completely inhibited AHR, eosinophil infiltration and mucus overproduction, and significantly reduced BALF IL-5. However, treatment with DXM alone after OVA challenge only partially inhibited AHR, eosinophil infiltration and mucus overproduction, and did not diminish BALF IL-5. Treatment with either DXM or anti-CD69 mAb did not alter the concentration of BALF GM-CSF. Conclusions: Anti-CD69 mAb treatment inhibits established airway inflammation as effectively as DXM pretreatment. This study provides a potential alternative therapeutic opportunity for the clinical management of asthma and its exacerbation.

Section: Fig 6 Effect Of Anti-cd69 Mab On Ova-induced Ahrsupporting

confidence: 81%

Anti-CD69 monoclonal antibody treatment inhibits airway inflammation in a mouse model of asthma

Dai

J. Zhejiang Univ. Sci. B

et al. 2015

The Journal of Immunology

“…This differential effect is not surprising knowing that the signaling pathways triggered by either cytokine in human basophils have been shown to be distinct (22). It suggests that through basophil activation IL-33 could affect preferentially the inflammatory Th17 axis of the immune response (23), relative to the pro-Th2 effect mediated by IL-3 (24).…”

Section: Discussionmentioning

confidence: 95%

IL-33 Activates Unprimed Murine Basophils Directly In Vitro and Induces Their In Vivo Expansion Indirectly by Promoting Hematopoietic Growth Factor Production

Schneider

Petit‐Bertron

Bricard

et al. 2009

128

IL-33, a new member of the IL-1 family, has been described as an important inducer of Th2 cytokines and mediator of inflammatory responses. In this study, we demonstrate that murine basophils sorted directly from the bone marrow, without prior exposure to IL-3 or FcεR cross-linking, respond to IL-33 alone by producing substantial amounts of histamine, IL-4, and IL-6. These cells express ST2 constitutively and generate a cytokine profile that differs from their IL-3-induced counterpart by a preferential production of IL-6. In vivo, IL-33 promotes basophil expansion in the bone marrow (BM) through an indirect mechanism of action depending on signaling through the βc chain shared by receptors for IL-3, GM-CSF, and IL-5. IL-3 can still signal through its specific βIL-3 chain in these mutant mice, which implies that it is not the unique growth-promoting mediator in this setup, but requires IL-5 and/or GMCSF. Our results support a major role of the latter growth factor, which is readily generated by total BM cells as well as sorted basophils in response to IL-33 along with low amounts of IL-3. Furthermore, GM-CSF amplifies IL-3-induced differentiation of basophils from BM cells, whereas IL-5 that is also generated in vivo, affects neither their functions nor their growth in vitro or in vivo. In conclusion, our data provide the first evidence that IL-33 not only activates unprimed basophils directly, but also promotes their expansion in vivo through induction of GM-CSF and IL-3.

The Journal of Immunology

“…PHIL mice have defective T cell migration to the lung and Th2 cytokine production in the absence of eosinophils, despite the delivery of in vitro-differentiated Th2 cells (4). Mice lacking the common bc receptor, required for the development of eosinophils, MC, and BAS, also have defects in T cell migration to the lung as well as Th2 T cell differentiation (48), although this may be due to a role for basophils in Th2 responses (14,15,49). At the same time, Ab blockade of CD4 + T cells in the lung reduces secretion of chemokines and Th2 cytokines as well as attenuates eosinophilic inflammation in the lung (7,8,50).…”

Section: Discussionmentioning

confidence: 99%

Computational and Experimental Analysis Reveals a Requirement for Eosinophil-Derived IL-13 for the Development of Allergic Airway Responses in C57BL/6 Mice

Walsh

Thakar

Stokes

et al. 2011

Eosinophils are found in the lungs of humans with allergic asthma, as well as in the lungs of animals in models of this disease. Increasing evidence suggests that these cells are integral to the development of allergic asthma in C57BL/6 mice. However, the specific function of eosinophils that is required for this event is not known. In this study, we experimentally validate a dynamic computational model and perform follow-up experimental observations to determine the mechanism of eosinophil modulation of T cell recruitment to the lung during development of allergic asthma. We find that eosinophils deficient in IL-13 were unable to rescue airway hyperresponsiveness, T cell recruitment to the lungs, and Th2 cytokine/chemokine production in ΔdblGATA eosinophil-deficient mice, even if Th2 cells were present. However, eosinophil-derived IL-13 alone was unable to rescue allergic asthma responses in the absence of competence of other IL-13–producing cells. We further computationally investigate the role of other cell types in the production of IL-13, which led to the various predictions including early and late pulses of IL-13 during airway hyperresponsiveness. These experiments suggest that eosinophils and T cells have an interdependent relationship, centered on IL-13, which regulates T cell recruitment to the lung and development of allergic asthma.