Following piroxicam treatment or infection with T. muris
, IFN-γ and IL-17A-driven intestinal inflammation correlated with elevated IL-13Rα2. Deletion of IL-13Rα2 abrogated IFN-γ and IL-17A and significantly attenuated the degree of inflammation in both models. These data suggest that IL-13Rα2 is directly responsible for the development of inflammation, as suggested in a different model of colitis25
. Alternatively, these observations suggest that IL-13Rα2 was blocking IL-1322, 24
, and that IL-13 functions as a negative regulator of IFN-γ and IL-17A. Following piroxicam treatment or T. muris
infection of il10−/−il13Rα2−/−
dKO mice, we observed evidence of increased IL-13 activity (increased ym-1 and arg-1 or elevated goblet cell and mucus responses, respectively) and decreased IFN-γ and IL-17A, supporting the latter model. Thus, increased IL-13 activity in the absence of IL-13Rα2 led us to hypothesize that IL-13Rα2 blocks the protective effects IL-13. We tested this hypothesis by neutralizing IL-13 in il10−/−il13Rα2−/−
dKO mice, which restored IFN-γ and IL-17A responses, inflammation and mortality following T. muris
infection. These observations clearly indicate that the balance between IL-13 and the IFN-γ/IL-17A axis tightly regulates the degree of intestinal inflammation. Furthermore these data also demonstrate that IL-13Rα2 is intricately involved in the regulation of this balance and consequently, the development of IBD.
Because CD and UC have distinct inflammatory etiologies, with Th1-Th17-associated Crohn’s disease developing in the small and large bowel38
and IL-13-mediated ulcerative colitis occurring primarily in the colon39
, the suppression of IL-13 activity by the decoy receptor may be a critical event in the genesis of Th1-Th17 driven inflammation in the gastrointestinal tract. In our studies, the enhanced IL-13 activity observed in the colon of il10−/−il13Rα2−/−
mice suppressed the development of Th1-Th17–associated colitis. These data present a new mechanism of IL-13-mediated control of Th1/17 responses. They may also explain why ulcerative colitis and Crohn’s disease are rarely if ever identified in the same individual40
, as the key inducer of UC (IL-13) appears to be a negative regulator of Th1-Th17-associated CD.
Interestingly, a recent paper by Shea-Donohue and colleagues41
showed that IL-13 and IL-13Rα2 are expressed much more in the colon than small intestine. Thus, changes in IL-13 and IL-13Rα2 expression might be expected to have a much larger impact on the development of Th1-Th17-mediated inflammation in the colon than in other areas of the gastrointestinal tract. However, the marked absence of IL-13Rα2 in the small bowel might also lead to increased IL-13 bioactivity in this region and thus provide critical protection from Th1-Th17-dependent colitis, while increasing the risk of IL-13-driven UC. Clinical findings support the notion that IL-13 may be protective in Crohn’s disease, as Crohn’s disease patients produce less IL-4 and IL-13 and their PBMC’s are hypo-responsive to IL-1342
The hypothesis that IL-13 can cross-regulate the development of Th17 cells is supported by the inverse relationship we observed between IL-17A and IL-13. Although IFNγ and IL-17A production was more marked in the absence of IL-10, they also increased when WT mice were treated with anti-IL-13, further supporting a role for IL-13 in the suppression of IFN-γ/IL-17A production in the gut. Together, these observations suggest that in addition to inducing goblet cell hyperplasia43
, epithelial cell turnover44
, and production of Relm-β (Fizz-2/Retnlb
, IL-13 also plays a key protective role in the gut by suppressing CD4+
Th1 and Th17 cell development33
. When viewed together, these studies reveal a novel protective pathway for IL-13 and its decoy in the control of Th1/Th17-mediated inflammation in the gastrointestinal tract.
In contrast to our findings, two related studies investigating the role of IL-13Rα2 in a model of chronic trinitrobenzene sulfonic acid (TNBS)-induced colitis concluded that IL-13Rα2 functions as a signaling receptor for IL-13 25, 26
. Using either a soluble IL-13Rα2-Fc protein or IL-13Rα2-specific small interfering RNA’s to block IL-13Rα2, they concluded that IL-13 signals through IL-13Rα2 and induces IL-13-dependent fibrosis. Although the TNBS model was not employed in our studies, we found no evidence that IL-13Rα2 was functioning as a signaling receptor for IL-13. In fact, our data suggested that IL-13Rα2 primarily blocks IL-13 effector functions, supporting its role as a decoy receptor. We concluded that by blocking IL-13 activity, IL-13Rα2 plays an indispensable role in the genesis of Th1/Th17-associated intestinal pathology in il10−/−
The explanation for the different conclusions is not clear, although the sIL-13Rα2-Fc blocker used in their studies binds IL-13, not IL-13Rα2; therefore it is not capable of distinguishing between IL-13Rα1 and IL-13Rα2-mediated effects. The use of small interfering RNAs in vivo may also have important off-target effects45
. Our studies with il13Rα2−/−
dKO mice all point to IL-13Rα2 functioning as a decoy receptor for IL-13 in the gastrointestinal tract.
In contrast to the well-known pathogenic properties of IL-13 46, 47
, to our knowledge, this is the first study to provide evidence of a tissue-protective role for IL-13 in the GI tract. A similar protective role for IL-13 has been described in the liver following ischemia/reperfusion injury48
and in the CNS following MOG33-55
. In both cases, pro-inflammatory cytokine production was suppressed, either following rIL-13 treatment or following the induction of IL-13 by IL-25, with hepatic Kupfer cells48
identified as the key targets of IL-13. It has previously been reported that IL-13 can abrogate Th1 development indirectly 50
, by modulating APC function (reviewed in 35, 51
); however, this is one of the first studies implicating IL-13 as a negative regulator of Th17 development in vivo.
Previously, using models of pulmonary and hepatic inflammation, we demonstrated that IL-13Rα2 is upregulated by IL-4 and IL-13 and suppressed by IFNγ in vivo52
. The soluble form of the IL-13Rα2 was also found in abundance in un-manipulated mice22
and consistent with our findings, was expressed at quite high levels in the colon41
. In the lung and liver the decoy IL-13Rα2 restricts the pro-fibrotic and pathogenic activities of IL-13 during allergic inflammation and chronic helminth infection22
. Therefore, in some circumstances, disrupting IL-13Rα2 might have unintended consequences such as exacerbating IL-13-driven diseases like allergic asthma or infection induced hepatic fibrosis 21, 46
. This report identifies a similar role for IL-13Rα2 in the intestine, however instead of restricting IL-13 and preventing IL-13 related pathology, our data suggest that IL-13Rα2 is key to generating IFNγ/IL-17A-driven inflammation and immunopathology in the bowel. The heightened susceptibility of IL-10-deficient mice to colitis is clearly controlled by this mechanism, as il10−/−
mice developed increased IL-13Rα2 responses and reduced IL-13 activity during T. muris
infection or following treatment with piroxicam. In both cases this led to the development of IFNγ/IL-17-associated colitis and intestinal inflammation. Consequently, reagents that specifically target and inhibit the IL-13 decoy receptor and enhance IL-13 effector function might offer a new strategy to prevent or reverse inflammatory bowel disease.