IL-33 induces Th17-mediated airway inflammation via mast cells in ovalbumin-challenged mice

Abstract

Allergic asthma is characterized by infiltration of eosinophils, elevated Th2 cytokine levels, airway hyperresponsiveness, and IgE. In addition to eosinophils, mast cells, and basophils, a variety of cytokines are also involved in the development of allergic asthma. The pivotal role of eosinophils in the progression of the disease has been a subject of controversy. To determine the role of eosinophils in the progression of airway inflammation, we sensitized and challenged BALB/c wild-type (WT) mice and eosinophil-deficient ΔdblGATA mice with ovalbumin (OVA) and analyzed different aspects of inflammation. We observed increased eosinophil levels and a Th2-dominant response in OVA-challenged WT mice. In contrast, eosinophil-deficient ΔdblGATA mice displayed an increased proportion of mast cells and a Th17-biased response following OVA inhalation. Notably, the levels of IL-33, an important cytokine responsible for Th2 immune deviation, were not different between WT and eosinophil-deficient mice. We also demonstrated that mast cells induced Th17-differentiation via IL-33/ST2 stimulation in vitro. These results indicate that eosinophils are not essential for the development of allergic asthma and that mast cells can skew the immune reaction predominantly toward Th17 responses via IL-33 stimulation.

The IL-33/ST2 axis augments effector T-cell responses during acute GVHD

“…A pro-inflammatory role for IL-33 was found in respiratory syncytial virus infection, 42 and neutralizing antibodies against ST2 attenuated lung inflammation. 35,43 A pro-inflammatory role for IL-33 was also reported in the pathogenesis of rheumatoid arthritis, 44 mast cell-induced airway inflammation, 12 allergic sensitization, 23 and inflammatory bowel disease. 26,45 Conversely, IL-33 was shown to protect against atherosclerosis through the induction of IL-5, 46 was cardioprotective, 1 promoted cardiac allograft survival, 22 and had either no effect on experimental autoimmune encephalomyelitis or even reduced its severity.…”

“…5,[12][13][14][15][16][17][18][19][20][21][22] Depending on the target tissue and cell types expressing ST2L, IL-33/ST2 signaling has established dual roles in promoting pro-inflammatory responses and conversely resolving inflammatory processes, similar to its family member IL-18.…”

Mast cell activation: A complex interplay of positive and negative signaling pathways

“…In mast cells, activation of IL-33R, either alone or simultaneously with FcεRI, leads to, or enhances, the production of TNF-α, IL-6, IL-13, MCP-1, MCP-3, and MIP-1α via the Src and MAPK cascade [49]. This activation mirrors enhanced in vivo mast cell response in a mast cell dependent model of psoriasis [50] and airway inflammation [51]. Indeed, IL-33 is highly expressed in asthmatics [52] …”

The role of IL-33/ST2L signals in the immune cells

“…Moreover, IL-33/ST2L stimulation induces Th17-differentiation on MCs in airway inflammation, which indicates MCs can skew the immune reaction predominantly toward Th17 responses via IL-33 [69]. IL-33 induces cytokines production by MCs through activation of signaling cascades that have distinct inducers depending on the cell type and cell in the phases, which reflect the distinct type of cytokine produced by MCs.…”