Mast cell responses in a mouse model of food allergy are regulated via a ST2/IL‐4 axis

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SUPPORTING INFORMATION
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DOI : 10.1111/all.162 57
Mast cell responses in a mouse model of food allergy are
regulated via a ST2/IL- 4 axis
To the Editor,
Allergen- induced mast cell (MC) activation is critical for the de-
velopment of food allergy. Recent evidence implicates the alarmin
cytokine, IL- 33, as a key player in regulating MC responses dur-
ing allergic inflammation. The IL- 33 receptor, ST2, is constitutively
expressed on MCs, and genetic polymorphisms within the IL- 33/
ST2 axis are strongly linked to disease susceptibility.1 Several re-
cent studies have demonstrated a critical role for IL- 33 in inducing
MC responses to food antigens, including decreased MC activation
and food allergy development in both epicutaneously- sensitized
ST2−/− mice2,3 and mice treated with anti- IL- 33 antibodies.2,4
Similarly, IL- 33- stimulated group 2 innate lymphoid cells can also
activate MCs in enterally- challenged mice.5 However, depend-
ing on the model of allergic sensitization (epicutaneous—with or
without t ape- stripping), divergent effects on MC activation, in-
testinal MC numbers, and anaphylaxis have been observed.2, 3
While epicutaneously- sensitized, tape- stripped ST2−/− mice were
protected from anaphylaxis due to decreased MC activation, no
changes in intestinal MC expansion were observed.2 In contrast , in
non- tape- stripped ST2−/− mice, both MC activation and intestinal
MC numbers were decreased.3
We sought to investigate the role of IL- 33 using a well-
established model of systemic sensitization to food antigens. Briefly,
wild- type Balb/c (WT) and ST2−/− mice were immunized i.p. with
chicken egg ovalbumin (OVA), followed by intragastric OVA chal-
lenges. Oral allergen exposure resulted in profuse allergic diarrhea
in sensitized WT mice (Figure 1A), accompanied by a robust antigen-
mediated IgE response (Figure 1B), significant MC accumulation in
the jejunum (Figure 1C), and increased MC activation (Figure 1D),
as indicated by elevated serum MC protease- 1 (MCPT- 1). In con-
trast, ST2−/− mice exhibited decreased diarrhea and MC responses
(Figure 1A–D). Similarly, the expression of the t ype 2 cytokine
genes, IL- 4 and IL- 13, was also reduced in the intestines of ST2−/−
mice (Figure 1E,F). In contrast, enhanced expression of IL- 33 was
observed in OVA- sensitized ST2−/− mice (Figure S1 A). A trend to-
wards increased expression of IFN- γ was also obser ved (Figure S1
B), suggesting that a decrease in type 2 cytokines may be accom-
panied by a parallel increase in type 1 cytokines. IL- 33 is critical for
the induction of allergen- specific Th2 cells.6,7 We therefore won-
dered whether systemic T cell responses may also be impaired in
the absence of ST2. As obser ved in Figure 1G–J, while splenocytes
from OVA- challenged WT mice secreted elevated levels of IL- 4, IL- 5
and IL- 13 in response to antigen restimulation, the production of
these cytokines was decreased in the ST2−/− group. Similarly, T cell
receptor- mediated polyclonally- induced type 2 cytokines were also
decreased in OVA- challenged ST2−/− mice (Figure S1 C–F ).
Considering the surprisingly low levels of T cell- derived IL- 4 in
the absence of IL- 33 signa ling and given that IL- 4 has been shown to
induce MC activation,8 we wondered whether the attenuated MC
responses in OVA- sensitized ST2−/− mice may be a consequence of
decreased IL- 4 produc tion. This is consistent with previous stud-
ies demonstrating decreased IL- 4 production in antigen- specific T
cells from ST2−/− mice.9 Furthermore, while we did not observe any
differences in baseline IL- 4 production from polyclonally stimu-
lated naïve WT or ST2−/− splenic T cells (Figure S2A and as has also
been observed previously9), IL- 4Rα expression was decreased in
both bone marrow- derived MCs (Figure S2B) and OVA- sensitized
CD4 T cells (Figure S2C) from ST2−/− mice. Lastly, the induction
of food allergy in this model has also been shown to be depen-
dent on IL- 4 with both antibody- mediated depletion and genetic
ablation resulting in the suppression of MC responses.10 To there-
fore further assess the role of IL- 4, we treated mice with IL- 4C to
boost IL- 4 levels in ST2−/− mice. To our surprise, IL- 4 treatment not
only amplified the effec ts of allergen challenge in W T animals, but
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