TY - JOUR
T1 - Goblet cell LRRC26 regulates BK channel activation and protects against colitis in mice
AU - Gonzalez-Perez, Vivian
AU - Martinez-Espinosa, Pedro L.
AU - Sala-Rabanal, Monica
AU - Bharadwaj, Nikhil
AU - Xia, Xiao Ming
AU - Chen, Albert C.
AU - Alvarado, David
AU - Gustafsson, Jenny K.
AU - Hu, Hongzhen
AU - Ciorba, Matthew A.
AU - Lingle, Christopher J.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Thaddeus Stappenbeck for useful discussions. This work was supported by the Lawrence C. Pakula, MD Inflammatory Bowel Disease Education & Innovation Fund IA-2018-10-IBD-2 (to V.G.-P.) and Grant GM-081748 (to C.J.L.). Kcnma1 knockout mice were kindly provided by Dr. Andrea Meredith, University of Maryland, Baltimore. We acknowledge Swedish Research Council Grant 2014-00366 (to J.K.G.) and Grant 2017-00958 for the generation of the mCherry-Muc2 transgenic mouse, which was kindly provided by Dr. Gunnar C. Hansson, University of Gothenburg, Sweden. Histology services were provided by the Washington University Digestive Research Core Center supported by Grant P30DK052574. Slide imaging was performed in a Hamamatsu Nanozoomer 2.0 hosted by the Hope Center for Neurological Disorders of the Washington University in St. Louis and supported by NIH shared Instrumentation Grant S10RR027552. Microbiota analysis was performed at the Washington University Genome Technology Access Center, which is partially supported by National Cancer Institute Cancer Center Support Grant P30 CA91842 and by Institute of Clinical and Translational Sciences/Clinical and Translational Science Award Grant UL1TR000448 from the National Center for Research Resources.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/1/19
Y1 - 2021/1/19
N2 - Goblet cells (GCs) are specialized cells of the intestinal epithelium contributing critically to mucosal homeostasis. One of the functions of GCs is to produce and secrete MUC2, the mucin that forms the scaffold of the intestinal mucus layer coating the epithelium and separates the luminal pathogens and commensal microbiota from the host tissues. Although a variety of ion channels and transporters are thought to impact on MUC2 secretion, the specific cellular mechanisms that regulate GC function remain incompletely understood. Previously, we demonstrated that leucine-rich repeat-containing protein 26 (LRRC26), a known regulatory subunit of the Ca2+-and voltage-activated K+ channel (BK channel), localizes specifically to secretory cells within the intestinal tract. Here, utilizing a mouse model in which MUC2 is fluorescently tagged, thereby allowing visualization of single GCs in intact colonic crypts, we show that murine colonic GCs have functional LRRC26-associated BK channels. In the absence of LRRC26, BK channels are present in GCs, but are not activated at physiological conditions. In contrast, all tested MUC2− cells completely lacked BK channels. Moreover, LRRC26-associated BK channels underlie the BK channel contribution to the resting transepithelial current across mouse distal colonic mucosa. Genetic ablation of either LRRC26 or BK pore-forming α-subunit in mice results in a dramatically enhanced susceptibility to colitis induced by dextran sodium sulfate. These results demonstrate that normal potassium flux through LRRC26-associated BK channels in GCs has protective effects against colitis in mice.
AB - Goblet cells (GCs) are specialized cells of the intestinal epithelium contributing critically to mucosal homeostasis. One of the functions of GCs is to produce and secrete MUC2, the mucin that forms the scaffold of the intestinal mucus layer coating the epithelium and separates the luminal pathogens and commensal microbiota from the host tissues. Although a variety of ion channels and transporters are thought to impact on MUC2 secretion, the specific cellular mechanisms that regulate GC function remain incompletely understood. Previously, we demonstrated that leucine-rich repeat-containing protein 26 (LRRC26), a known regulatory subunit of the Ca2+-and voltage-activated K+ channel (BK channel), localizes specifically to secretory cells within the intestinal tract. Here, utilizing a mouse model in which MUC2 is fluorescently tagged, thereby allowing visualization of single GCs in intact colonic crypts, we show that murine colonic GCs have functional LRRC26-associated BK channels. In the absence of LRRC26, BK channels are present in GCs, but are not activated at physiological conditions. In contrast, all tested MUC2− cells completely lacked BK channels. Moreover, LRRC26-associated BK channels underlie the BK channel contribution to the resting transepithelial current across mouse distal colonic mucosa. Genetic ablation of either LRRC26 or BK pore-forming α-subunit in mice results in a dramatically enhanced susceptibility to colitis induced by dextran sodium sulfate. These results demonstrate that normal potassium flux through LRRC26-associated BK channels in GCs has protective effects against colitis in mice.
KW - LRRC26 | Ca-activated K channels | epithelial cells | DSS-induced colitis | inflammatory bowel disease
UR - http://www.scopus.com/inward/record.url?scp=85099158035&partnerID=8YFLogxK
U2 - 10.1073/pnas.2019149118
DO - 10.1073/pnas.2019149118
M3 - Article
C2 - 33431687
AN - SCOPUS:85099158035
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 3
M1 - e2019149118
ER -