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RESEARCH

NEUROIMMUNOLOGY observed in the interfollicular region (24), para-
cortical region, and the medulla of the draining
b -adrenergic receptor–mediated mLN, which are anatomical sites where sympa-
thetic adrenergic neurons are abundant (12, 13)
2
(Fig.1, I to K, and fig.S1, E and F).
negative regulation of group 2 innate development at steady state, b 2 AR-sufficient
To analyze the effect of b 2 AR signaling on ILC2
lymphoid cell responses (Adrb2 +/+ ) and b 2 AR-deficient (Adrb2 −/− ) mice
−/−
+/+
were analyzed. Adrb2
and Adrb2
mice had
comparable numbers of ILC2 progenitors (ILC2Ps)
1
1
Saya Moriyama, Jonathan R. Brestoff, 1,2 Anne-Laure Flamar, Jesper B. Moeller, 1,3 (25) in the bone marrow (BM, fig. S2A). Addi-
−/−
+/+
tionally, Adrb2
and Adrb2
1
1
1
Christoph S. N. Klose, Lucille C. Rankin, Naomi A. Yudanin, Laurel A. Monticelli, 1 mice had sim-
1
4
1
Gregory Garbès Putzel, Hans-Reimer Rodewald, David Artis * ilar frequencies of all ILC subsets in mLNs and
in SILP (fig. S2, B to D), indicating that b 2 AR
deficiency does not result in impaired ILC2 de-
The type 2 inflammatory response is induced by various environmental and infectious velopment or homeostasis at steady state.
stimuli. Although recent studies identified group 2 innate lymphoid cells (ILC2s) as potent
Next, we examined whether b 2 AR signaling
sources of type 2 cytokines, the molecular pathways controlling ILC2 responses are
regulates ILC2 responses and type 2 inflamma-
incompletely defined. Here we demonstrate that murine ILC2s express the b 2 -adrenergic
tion after exposure to the gastrointestinal hel-
receptor (b 2 AR) and colocalize with adrenergic neurons in the intestine. b 2 AR deficiency
minth Nippostrongylus brasiliensis.Thisinfection
resulted in exaggerated ILC2 responses and type 2 inflammation in intestinal and lung
induces potent ILC2 responses that play an im-
tissues. Conversely, b 2 AR agonist treatment was associated with impaired ILC2 responses and
portant role in the expulsion of the parasite
reduced inflammation in vivo. Mechanistically, we demonstrate that the b 2 AR pathway is a
through production of IL-5 and IL-13 (10, 26, 27).
cell-intrinsic negative regulator of ILC2 responses through inhibition of cell proliferation After infection, Adrb2 −/− mice exhibited increased
and effector function. Collectively, these data provide the first evidence of a neuronal- frequencies and numbers of ILC2s and increased Downloaded from
derived regulatory circuit that limits ILC2-dependent type 2 inflammation.
numbers of IL-13–producing ILC2s, but compara-
ble frequencies of ILC1s and ILC3s, in mLNs and
he type 2inflammatoryresponseisahighly ever, our knowledge of the complex interactions in SILP compared to Adrb2 +/+ mice (Fig.2,Aand
conserved module of the innate and adap- between the nervous system and ILCs in the con- B, and fig. S2E). The expression of inflammatory
tive immune system that is elicited after text of type 2 inflammation is still limited. RNA cytokines encoded by genes Il25, Il33,and Tslp,
exposure to infectious and environmental sequencing (RNA-seq) of sorted murine ILC sub- which stimulate ILC2s, was comparable between
T triggers, such as helminth infections, al- sets revealed that small intestinal (SI) ILC2s ex- Adrb2 +/+ and Adrb2 −/− mice in the SI after infec-
lergens, venoms, and other stimuli (1–3). The hall- hibited higher levels of the b 2 AR gene (Adrb2) tion (fig. S2F). However, exaggerated eosino-
marksoftype2responsesinclude activation of mRNA expression compared to SI ILC3s, but lower philia and goblet cell hyperplasia (Fig. 2, C and http://science.sciencemag.org/
Thelper2(T H 2) cells and release of type 2 cyto- levels of other adrenergic receptors (Fig. 1A). D) and reduced worm burdens (Fig. 2E) were
kines, such as interleukin-4 (IL-4), IL-5, IL-9, and Consistent with these results, ILC2s sorted from observed in Adrb2 −/− mice. Of note, the amount
IL-13; production of immunoglobulin E (IgE); and SI lamina propria (SILP), gut-draining mesen- of norepinephrine in the SI was comparable at
the activation of multiple effector cells, such as teric lymph node (mLN), colon LP, and lung ex- 0, 4, and 7 days postinfection (fig. S2G), suggest-
basophils, mast cells, and eosinophils. This cas- hibited higher levels of Adrb2 mRNA expression ing that expression of this ligand is not altered
cade of immunologic events is associated with compared to SILP ILC3s (Fig. 1B and fig. S1A). during infection. Notably, although ILC2s still
increased mucus production from goblet cells ILC2s from mesenteric white adipose tissue ex- expressed Adrb2 after infection, expression was
and induction of smooth-muscle contractility that hibited lower levels of Adrb2 mRNA expression at a lower level than observed in naive mice (fig. on March 1, 2018
contributes to the elimination of pathogens or compared to ILC2s from other tissue. We also S2H), suggesting that ILC2-intrinsic b 2 AR ex-
+
allergic stimuli (4, 5). Recent studies identified detected ADRB2 mRNA in ILC2s and CD4 Tcells pression is dynamically regulated in response to
group 2 innate lymphoid cells (ILC2s) as a potent sorted from human lung and peripheral blood inflammatory cues within the tissue microen-
source of type 2 cytokines that contribute to the mononuclear cells (Fig. 1C). These results show vironment. Taken together, these results indicate
type 2 inflammatory responses (5–11). Although that the b 2 AR gene is expressed in murine and that the b 2 AR pathway may be an important neg-
considerable advances have been made to define human ILC2s. ative regulator of ILC2 responses.
the cytokines, growth factors, and environmental Examination of the localization of ILC2s (de- Given that b 2 AR-deficient mice had exaggerated
–
–
+
+
stimuli that trigger ILC2 responses, the regula- fined as KLRG1 Bcl11b CD3e NKp46 )and adre- ILC2 responses, we next sought to test whether
tory mechanisms that constrain ILC2 responses nergic neurons [marked by tyrosine hydroxylase treatment with a b 2 AR agonist, clenbuterol, would
and type 2 inflammation at mucosal sites remain (TH) expression] in the SI microenvironment inhibit ILC2 responses and dampen type 2 in-
incompletely understood. revealed that ILC2s were found in close prox- flammation. Although the proportion of ILC sub-
+
Mucosal and lymphoid tissues are highly in- imity to TH neurons in the villi and submucosa sets was not changed by b 2 AR agonist treatment
nervated (12–14), and immune cells—including butnot in themuscularis(Fig. 1, D and E, and at steady state (fig. S2I), b 2 AR agonist–treated
mast cells, macrophages, ILCs, and T cells—can fig. S1B). To further examine this, we generated wild-type C57BL/6 (B6) mice exhibited signif-
be regulated by neuronal-derived bioactive mol- Il13–fate mapping mice by crossing Il13 cre and icantly fewer ILC2s in the mLNs compared to
ecules in certain circumstances (15–23). How- Ai14 (tdTomato) mice and found that ILC2s vehicle-treated mice after N. brasiliensis infec-
+
+
–
(defined as KLRG1 tdTomato CD3e )colocalize tion (Fig. 2F). Further, agonist treatment was
1 Jill Roberts Institute for Research in Inflammatory Bowel with TH neurons (Fig. 1F and fig. S1, C and D). associated with significantly fewer IL-5– and
+
Disease, Joan and Sanford I. Weill Department of Medicine, Notably, the highest expression levels of genes IL-13–producing ILC2s, reduced eosinophilia,
Department of Microbiology and Immunology, Weill Cornell
Medicine, Cornell University, New York, NY 10021, USA. encoding enzymes involved in norepinephrine and diminished goblet cell responses (Fig. 2, G
2 Department of Pathology and Immunology, Washington synthesis, Th and Dbh (dopamine b-hydroxylase), to I, and fig. S2J). Consistent with these results,
University School of Medicine, St. Louis, MO 63110, USA. were found in the parenchyma fraction in the agonist-treated mice had significantly higher
3 Department of Molecular Medicine, University of Southern
Denmark, Odense, Denmark. Division of Cellular Immunology, SI (Fig. 1, G and H), which collectively suggests worm burdens (Fig. 2J). We also treated the mice
4
German Cancer Research Center (DKFZ), Heidelberg, Germany. that ILC2s may respond to neuronal-derived with another b 2 AR agonist, salmeterol, during
*Corresponding author. Email: dartis@med.cornell.edu norepinephrine, a b 2 AR ligand. ILC2s were also N. brasiliensis infection and found reduced
Moriyama et al., Science 359, 1056–1061 (2018) 2 March 2018 1of6