Delayed Goblet Cell Hyperplasia, Acetylcholine Receptor Expression, and Worm Expulsion in SMC-Specific IL-4Rα–Deficient Mice

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Abstract
Interleukin 4 receptor α (IL-4Rα) is essential for effective clearance of gastrointestinal nematode infections. Smooth muscle cells are considered to play a role in the type 2 immune response–driven expulsion of gastrointestinal nematodes. Previous studies have shown in vitro that signal transducer and activator of transcription 6 signaling in response to parasitic nematode infection significantly increases smooth muscle cell contractility. Inhibition of the IL-4Rα pathway inhibits this response. How this response manifests itself in vivo is unknown. In this study, smooth muscle cell IL-4Rα–deficient mice (SM-MHCCreIL-4Rα−/lox) were generated and characterized to uncover any role for IL-4/IL-13 in this non–immune cell type in response to Nippostrongylus brasiliensis infection. IL-4Rα was absent from α-actin–positive smooth muscle cells, while other cell types showed normal IL-4Rα expression, thus demonstrating efficient cell-type–specific deletion of the IL-4Rα gene. N. brasiliensis–infected SM-MHCCreIL-4Rα−/lox mice showed delayed ability to resolve infection with significantly prolonged fecal egg recovery and delayed worm expulsion. The delayed expulsion was related to a delayed intestinal goblet cell hyperplasia, reduced T helper 2 cytokine production in the mesenteric lymph node, and reduced M3 muscarinic receptor expression during infection. Together, these results demonstrate that in vivo IL-4Rα–responsive smooth muscle cells are beneficial for N. brasiliensis expulsion by coordinating T helper 2 cytokine responses, goblet hyperplasia, and acetylcholine responsiveness, which drive smooth muscle cell contractions. Intestinal parasitic worm infections are a major public health concern, with more than 1 billion people infected worldwide. Symptoms associated with these infections are similar to that of other intestinal illnesses, including irritable bowel syndrome. It is likely that the immune response required to expel the worm can also, when activated inappropriately, cause the symptoms of irritable bowel syndrome. This makes understanding parasitic worm infections important in their own right and also as a model for other intestinal illnesses. In previous studies, we demonstrated the crucial importance of interleukin 4 receptor α (IL-4Rα) responsiveness for worm expulsion in global IL-4Rα–deficient mice. In this study, we specifically addressed the role of IL-4Rα responsiveness in a novel smooth muscle cell–specific IL-4Rα–deficient mouse model. These mice showed decreased ability to control the worm infection, with delayed expulsion and reduced protective immune responses. These data provide compelling evidence for smooth muscle cell IL-4Rα being an important coordinator of both the immune and physiological responses to intestinal worm infections. A proposed model is suggested with IL-4Rα responsiveness on smooth muscle cells coordinating T helper 2 cytokine responses, goblet hyperplasia, and acetylcholine-driven smooth muscle contractions for optimal worm expulsion.