BMP signaling in the intestinal epithelium drives a critical feedback loop to restrain IL-13–driven tuft cell hyperplasia

Abstract

The intestinal tract is a common site for various types of infections including viruses, bacteria, and helminths, each requiring specific modes of immune defense. The intestinal epithelium has a pivotal role in both immune initiation and effector stages, which are coordinated by lymphocyte cytokines such as IFNγ, IL-13, and IL-22. Here, we studied intestinal epithelial immune responses using organoid image analysis based on a convolutional neural network, transcriptomic analysis, and in vivo infection models. We found that IL-13 and IL-22 both induce genes associated with goblet cells, but the resulting goblet cell phenotypes are dichotomous. Moreover, only IL-13–driven goblet cells are associated with classical NOTCH signaling. We further showed that IL-13 induces the bone morphogenetic protein (BMP) pathway, which acts in a negative feedback loop on immune type 2–driven tuft cell hyperplasia. This is associated with inhibiting Sox4 expression to putatively limit the tuft cell progenitor population. Blocking ALK2, a BMP receptor, with the inhibitor dorsomorphin homolog 1 (DMH1) interrupted the feedback loop, resulting in greater tuft cell numbers both in vitro and in vivo after infection with Nippostrongylus brasiliensis . Together, this investigation of cytokine effector responses revealed an unexpected and critical role for the BMP pathway in regulating type 2 immunity, which can be exploited to tailor epithelial immune responses.

c-MAF coordinates enterocyte zonation and nutrient uptake transcriptional programs

“…BMP signaling promotes zonation of enterocytes and restricts tuft cell numbers at steady state (SS) and during infection (Beumer et al, 2022;Lindholm et al, 2022). Our results designate c-MAF as a downstream transcriptional mediator that controls both functions.…”

Vibrio choleraeArrests Intestinal Epithelial Proliferation through T6SS-dependent Activation of the Bone Morphogenetic Protein Pathway

“…Unlike fly guts which rely on germline-encoded innate defenses, zebrafish intestines also possess lymphocyte-based adaptive defenses that impact host responses to symbiotic and pathogenic microbes [76][77][78][79][80][81][82] . Recent studies reveal an immune-modulatory role of BMP in the vertebrate intestine [83][84][85] . In both human and mouse colons, epithelial-specific BMP activity limits expression of pro-inflammatory genes including a number of chemokines and cytokines and suppresses infiltration of macrophages and neutrophils 84,85 .…”

Compound C Inhibits Ovarian Cancer Progression via PI3K-AKT-mTOR-NFκB Pathway

“…The role of CC as an activator or inhibitor of PI3K-AKT-mTOR-NFκB pathways is contextual not only disease-specific but are also model system-specific with substantial technical variabilities in the studies reporting such role [ 65 , 72 , 73 , 74 ]. Furthermore, known chemical modifications and/or homologs of CC were designed to enhance its effects on BMP/BMP receptors as an anti-fibrotic agent in pulmonary fibrosis and diabetic nephropathy [ 75 , 76 , 77 ]. However, the therapeutic efficacy of these molecules on OvCa cells was understudied with only two studies reporting the therapeutic potential of CC in OvCa [ 32 , 40 ].…”