The IL-33 receptor (ST2) regulates early IL-13 production in fungus-induced allergic airway inflammation

Abstract

Allergic airway inflammation (AAI) in response to environmental antigens is an increasing medical problem, especially in the Western world. Type 2 interleukins (IL) are central in the pathological response but their importance and cellular source(s) often rely on the particular allergen. Here, we highlight the cellular sources and regulation of the prototypic type 2 cytokine, IL-13, during the establishment of AAI in a fungal infection model using Cryptococcus neoformans. IL-13 reporter mice revealed a rapid onset of IL-13 competence within innate lymphoid cells type 2 (ILC2) and IL-33R(+) T helper (Th) cells. ILC2 showed IL-33-dependent proliferation upon infection and significant IL-13 production. Th cells essentially required IL-33 to become either GATA3(+) or GATA3(+)/Foxp3(+) hybrids. GATA3(+) Th cells almost exclusively contributed to IL-13 production but hybrid GATA3(+)/Foxp3(+) Th cells did not. In addition, alveolar macrophages upregulated the IL-33R and subsequently acquired a phenotype of alternative activation (Ym1(+), FIZZ1(+), and arginase-1(+)) linked to type 2 immunity. Absence of adaptive immunity in rag2(-/-) mice resulted in attenuated AAI, revealing the need for Th2 cells for full AAI development. Taken together, in pulmonary cryptococcosis ILC2 and GATA3(+) Th2 cells produce early IL-13 largely IL-33R-dependent, thereby promoting goblet cell metaplasia, pulmonary eosinophilia, and alternative activation of alveolar macrophages.

Bone marrow type 2 innate lymphoid cells: a local source of interleukin‐5 in interleukin‐33‐driven eosinophilia

“…Interleukin‐33‐induced eotaxin‐2/CCL24 production has previously been investigated in mice, where IL‐33 was reported to polarize alveolar macrophages toward an alternatively activated phenotype that were able to produce high levels of eotaxin‐2/CCL24 (and TARC/CCL17) in vitro in response to IL‐33 stimulation together with IL‐13 . Eotaxin‐2/CCL24 expression has been described to be dependent on IL‐13, and we and others have previously shown that IL‐13 is produced by airway ILC2s in response to IL‐33 stimulation in vivo . It is possible that airway ILC2s are contributing to the expression of eotaxin‐2/CCL24 by producing IL‐13 in our model of IL‐33‐induced eosinophilia.…”

Lung epithelium: barrier immunity to inhaled fungi and driver of fungal-associated allergic asthma

“…Leukocytes bearing IL-33R respond to this alarm and propagate a type-2 immune response. Sub-lethal infection of mice with Cryptococcus neoformans leads to allergic inflammation that is dependent on IL-33R [20]. Interestingly, IL-33 expression is restricted to type-2 alveolar cells in Cryptococcus infected lungs [21].…”

Antifungal Innate Immunity: A Perspective from the Last 10 Years

“…For instance, IL-33-producing ILC2 cells were shown to have a detrimental role in pulmonary immunity against C. neoformans [124] and in patients with severe asthma associated with fungal sensitization [125]. Similar detrimental roles of IL-13-producing ILC2s were demonstrated in a mouse model of C. neoformans -induced airway inflammation [126] and in patients with Aspergillus -mediated chronic sinusitis [127]. Interestingly, prostaglandin I2 can reduce the number of Th2-expressing ILC2 in the lung, such as IL-13 and IL-5, and could potentially be exploited as a therapeutic strategy in this context [128].…”