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Crth2 receptor signaling down‐regulates lipopolysaccharide‐induced NF‐αB activation in murine macrophages via changes in intracellular calcium
Author(s) -
Diwakar Bastihalli T.,
Yoast Ryan,
Nettleford Shaneice,
Qian Fenghua,
Lee TaiJung,
Berry Svanjita,
Huffnagle Ian,
Rossi Randall M.,
Trebak Mohamed,
Paulson Robert F.,
Prabhu K. Sandeep
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201802608r
Subject(s) - proinflammatory cytokine , microbiology and biotechnology , chemistry , prostaglandin d2 , inflammation , allergic inflammation , receptor , prostaglandin , signal transduction , zymosan , biology , immunology , biochemistry , in vitro
Prostaglandin D 2 and its cyclopentenone metabolites [cyclopentenone prostaglandins (CyPGs)], Δ 12 prostaglandin J 2 and 15‐deoxy‐Δ 12, 14 ‐prostaglandin J 2 , 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 D 2 increased Ca 2+ influx through store‐operated Ca 2+ 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 Ca 2+ ‐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