TY - JOUR
T1 - Crth2 receptor signaling down-regulates lipopolysaccharide-induced NF-αB activation in murine macrophages via changes in intracellular calcium
AU - Diwakar, Bastihalli T.
AU - Yoast, Ryan
AU - Nettleford, Shaneice
AU - Qian, Fenghua
AU - Lee, Tai Jung
AU - Berry, Svanjita
AU - Huffnagle, Ian
AU - Rossi, Randall M.
AU - Trebak, Mohamed
AU - Paulson, Robert F.
AU - Prabhu, K. Sandeep
N1 - Funding Information:
The authors thank Drs. Connie Rogers and Ramesh Ramachandran (Pennsylvania State University, State College, PA, USA) for their help with the MicroBeta microplate counter and fluorescent microscope, respectively. ES cells were from the Trans‐U.S. National Institutes of Health (NIH) Knock‐Out Mouse Project (KOMP) Repository. NIH National Human Genome Research Institute grants to Velocigene at Regeneron, Inc. (U01HG004085), the Complementary Sex Determination (CSD) Consortium (U01HG004080), and KOMP Repository at University of California‐Davis (Davis, CA, USA) and Children's Hospital Oakland Research Institute (CHORI) (U42RR024244) funded the program to generate the gene‐targeted ES cells. These studies were funded, in part, by Public Health Service (PHS) grants from the NIH National Institute of Diabetes and Digestive and Kidney Diseases (DK077152) and Office of Dietary Supplements, and U.S. Department of Agriculture (USDA) Hatch Funds (PENO 4605, Accession 1010021 to K.S.P., DK080040; PENO 4581, Accession 1005468 to R.F.P.). The authors declare no conflicts of interest.
Funding Information:
The authors thank Drs. Connie Rogers and Ramesh Ramachandran (Pennsylvania State University, State College, PA, USA) for their help with the MicroBeta microplate counter and fluorescent microscope, respectively. ES cells were from the Trans-U.S. National Institutes of Health (NIH) Knock-Out Mouse Project (KOMP) Repository. NIH National Human Genome Research Institute grants to Velocigene at Regeneron, Inc. (U01HG004085), the Complementary Sex Determination (CSD) Consortium (U01HG004080), and KOMP Repository at University of California-Davis (Davis, CA, USA) and Children's Hospital Oakland Research Institute (CHORI) (U42RR024244) funded the program to generate the gene-targeted ES cells. These studies were funded, in part, by Public Health Service (PHS) grants from the NIH National Institute of Diabetes and Digestive and Kidney Diseases (DK077152) and Office of Dietary Supplements, and U.S. Department of Agriculture (USDA) Hatch Funds (PENO 4605, Accession 1010021 to K.S.P., DK080040; PENO 4581, Accession 1005468 to R.F.P.). The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Prostaglandin D2 and its cyclopentenone metabolites [cyclopentenone prostaglandins (CyPGs)], Δ12prostaglandin J2 and 15-deoxy-Δ12, 14-prostaglandin J2, act through2GPCRs, d-type prostanoid 1 and the chemoattractant receptor homologous molecule expressed on type 2 T-helper cells (Crth2). In addition to its role in allergy and asthma, the role of Crth2 in the resolution of inflammation, to mediate the proresolving functions of endogenous CyPGs, is not well understood. We investigated the regulation of LPS or zymosan-induced inflammatory response by signals from the Crth2 receptor in macrophages that lack Crth2 expression [knockout (KO)]. Increased expression of proinflammatory genes, including Tnf-α, was observed in Crth2 KO cells. Targeting the endogenous biosynthetic pathway of CyPGs with indomethacin or HQL79, which inhibit cyclooxygenases or hematopoietic prostaglandin D synthase, respectively, or use of Crth2 antagonists recapitulated the proinflammatory phenotype as in Crth2 KO cells. Ligand-dependent activation of Crth2 by 13, 14-dihydro-15-keto-prostaglandin D2 increased Ca2+ influx through store-operated Ca2+ entry (SOCE) accompanied by the up-regulation of stromal interaction molecule 1 and calcium release-activated calcium modulator 1 expression, suggesting that the proresolution effects of CyPG-dependent activation of SOCE could be mediated by Crth2 during inflammation. Interestingly, Crth2 signaling down-regulated the Ca2+-regulated heat stable protein 1 that stabilizes Tnf-α mRNA via the increased expression of microRNA 155 to dampen inflammatory responses triggered through the TNF-α-NF-αB axis. In summary, these studies present a novel regulatory role for Crth2 during inflammatory response in macrophages.—Diwakar, B. T., Yoast, R., Nettleford, S., Qian, F., Lee, T.-J., Berry, S., Huffnagle, I., Rossi, R. M., Trebak, M., Paulson, R. F., Prabhu, K. S. Crth2 receptor signaling down-regulates lipopolysaccharide-induced NF-αB activation in murine macrophages via changes in intracellular calcium. FASEB J. 33, 12838–12852 (2019). www.fasebj.org.
AB - Prostaglandin D2 and its cyclopentenone metabolites [cyclopentenone prostaglandins (CyPGs)], Δ12prostaglandin J2 and 15-deoxy-Δ12, 14-prostaglandin J2, act through2GPCRs, d-type prostanoid 1 and the chemoattractant receptor homologous molecule expressed on type 2 T-helper cells (Crth2). In addition to its role in allergy and asthma, the role of Crth2 in the resolution of inflammation, to mediate the proresolving functions of endogenous CyPGs, is not well understood. We investigated the regulation of LPS or zymosan-induced inflammatory response by signals from the Crth2 receptor in macrophages that lack Crth2 expression [knockout (KO)]. Increased expression of proinflammatory genes, including Tnf-α, was observed in Crth2 KO cells. Targeting the endogenous biosynthetic pathway of CyPGs with indomethacin or HQL79, which inhibit cyclooxygenases or hematopoietic prostaglandin D synthase, respectively, or use of Crth2 antagonists recapitulated the proinflammatory phenotype as in Crth2 KO cells. Ligand-dependent activation of Crth2 by 13, 14-dihydro-15-keto-prostaglandin D2 increased Ca2+ influx through store-operated Ca2+ entry (SOCE) accompanied by the up-regulation of stromal interaction molecule 1 and calcium release-activated calcium modulator 1 expression, suggesting that the proresolution effects of CyPG-dependent activation of SOCE could be mediated by Crth2 during inflammation. Interestingly, Crth2 signaling down-regulated the Ca2+-regulated heat stable protein 1 that stabilizes Tnf-α mRNA via the increased expression of microRNA 155 to dampen inflammatory responses triggered through the TNF-α-NF-αB axis. In summary, these studies present a novel regulatory role for Crth2 during inflammatory response in macrophages.—Diwakar, B. T., Yoast, R., Nettleford, S., Qian, F., Lee, T.-J., Berry, S., Huffnagle, I., Rossi, R. M., Trebak, M., Paulson, R. F., Prabhu, K. S. Crth2 receptor signaling down-regulates lipopolysaccharide-induced NF-αB activation in murine macrophages via changes in intracellular calcium. FASEB J. 33, 12838–12852 (2019). www.fasebj.org.
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UR - http://www.scopus.com/inward/citedby.url?scp=85074379154&partnerID=8YFLogxK
U2 - 10.1096/fj.201802608R
DO - 10.1096/fj.201802608R
M3 - Article
C2 - 31518163
AN - SCOPUS:85074379154
SN - 0892-6638
VL - 33
SP - 12838
EP - 12852
JO - FASEB Journal
JF - FASEB Journal
IS - 11
ER -