TY - JOUR
T1 - IL-17RA signaling promotes the dedifferentiation of Paneth progenitors through ADAM17 to regenerate gut epithelium post-irradiation
AU - Kempen, Cody G.
AU - Singh, Ankita
AU - Breau, Keith A.
AU - Tariq, Hafiz I.
AU - Yu, Yangle
AU - Gaudino, Stephen J.
AU - Bahadur, Tej
AU - Orzechowska-Licari, Emilia
AU - Eskiocak, Onur
AU - Shiomitsu, Kiyoshi
AU - Blumberg, Richard
AU - Denoya, Paula
AU - Martin, Rebecca
AU - Bialkowska, Agnieszka B.
AU - Beyaz, Semir
AU - Magness, Scott T.
AU - Hearing, Patrick
AU - Kim, Hwan Keun
AU - Sheridan, Brian S.
AU - Dempsey, Peter
AU - Kumar, Pawan
N1 - Publisher Copyright:
© The Author(s) 2026.
PY - 2026/12
Y1 - 2026/12
N2 - Paneth cells and their antimicrobial products are critical in mediating small intestinal host defense under homeostatic conditions and after injury or infection. In addition, Paneth cells have also been shown to gain stem-like properties and repropagate intestinal crypts after intestinal injury. The specific role of intestinal IL-17A or its receptor (IL-17RA) signaling in Paneth cells to gain stem-like features has yet to be investigated. Using Paneth cell-specific IL-17RA (Il17rafl/fl;Defa6-cre) knockout mice, anti-IL-17A neutralizing studies and lineage tracer (Defa6-cre;mT/mG) mice, we show that after injury IL-17RA signaling is required for Paneth cell to gain stem-like properties to regenerate the intestinal epithelium. Increased susceptibility of Il17rafl/fl;Defa6-cre mice is associated with reduced expression Adam17 in the terminal ileum. Adam17 overexpression in Il17rafl/fl;Defa6-cre mice rescues the epithelial regeneration defect in these mice. IL-17A induces Nox1 in Paneth cells and H2O2 induces ADAM17 enzymatic activity. Finally, using Paneth cell-specific Adam17 (Adam17fl/fl;Defa6-cre) knockout mice, we show that ADAM17 in Paneth cells is required for tissue regeneration. Collectively, our data reveal an essential role of the IL-17RA-ADAM17 pathways in Paneth cells for tissue regeneration.
AB - Paneth cells and their antimicrobial products are critical in mediating small intestinal host defense under homeostatic conditions and after injury or infection. In addition, Paneth cells have also been shown to gain stem-like properties and repropagate intestinal crypts after intestinal injury. The specific role of intestinal IL-17A or its receptor (IL-17RA) signaling in Paneth cells to gain stem-like features has yet to be investigated. Using Paneth cell-specific IL-17RA (Il17rafl/fl;Defa6-cre) knockout mice, anti-IL-17A neutralizing studies and lineage tracer (Defa6-cre;mT/mG) mice, we show that after injury IL-17RA signaling is required for Paneth cell to gain stem-like properties to regenerate the intestinal epithelium. Increased susceptibility of Il17rafl/fl;Defa6-cre mice is associated with reduced expression Adam17 in the terminal ileum. Adam17 overexpression in Il17rafl/fl;Defa6-cre mice rescues the epithelial regeneration defect in these mice. IL-17A induces Nox1 in Paneth cells and H2O2 induces ADAM17 enzymatic activity. Finally, using Paneth cell-specific Adam17 (Adam17fl/fl;Defa6-cre) knockout mice, we show that ADAM17 in Paneth cells is required for tissue regeneration. Collectively, our data reveal an essential role of the IL-17RA-ADAM17 pathways in Paneth cells for tissue regeneration.
UR - https://www.scopus.com/pages/publications/105034224460
U2 - 10.1038/s41467-026-70479-z
DO - 10.1038/s41467-026-70479-z
M3 - Article
C2 - 41844615
AN - SCOPUS:105034224460
SN - 2041-1723
VL - 17
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4091
ER -