The selective estrogen receptor modulator raloxifene inhibits neutrophil extracellular trap formation.
Raloxifene is a selective estrogen receptor modulator typically prescribed for the prevention/treatment of osteoporosis in postmenopausal women. Although raloxifene is known to have anti-inflammatory properties, its effect on human neutrophils, the primary phagocytic leukocytes of the immune system,...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2016-12-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00566/full |
| _version_ | 1819048959387107328 |
|---|---|
| author | Roxana Flores Simon Döhrmann Christina Schaal Abdul Hakkim Victor Nizet Victor Nizet Victor Nizet Ross Corriden |
| author_facet | Roxana Flores Simon Döhrmann Christina Schaal Abdul Hakkim Victor Nizet Victor Nizet Victor Nizet Ross Corriden |
| author_sort | Roxana Flores |
| collection | DOAJ |
| description | Raloxifene is a selective estrogen receptor modulator typically prescribed for the prevention/treatment of osteoporosis in postmenopausal women. Although raloxifene is known to have anti-inflammatory properties, its effect on human neutrophils, the primary phagocytic leukocytes of the immune system, remain poorly understood. Here, through a screen of pharmacologically active small molecules, we find that raloxifene prevents neutrophil cell death in response to the classical activator phorbol 12-myristate 13-acetate (PMA), a compound known to induce formation of DNA-based neutrophil extracellular traps (NETs). Inhibition of PMA-induced NET production by raloxifene was confirmed using quantitative and imaging-based assays. Human neutrophils from both male and female donors express the nuclear estrogen receptors ERα and ERβ, known targets of raloxifene. Like raloxifene, selective antagonists of these receptors inhibit PMA-induced NET production. Furthermore, raloxifene inhibited PMA-induced ERK phosphorylation but not reactive oxygen species (ROS) production, pathways known to be key modulators of NET production. Finally, we found that raloxifene inhibited PMA-induced, NET-based killing of the leading human bacterial pathogen, methicillin-resistant Staphylococcus aureus (MRSA). Our results reveal that raloxifene is a potent modulator of neutrophil function and NET production. |
| first_indexed | 2024-12-21T11:24:32Z |
| format | Article |
| id | doaj.art-051502abe0ce4c01a8042a76113d507d |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-21T11:24:32Z |
| publishDate | 2016-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-051502abe0ce4c01a8042a76113d507d2022-12-21T19:05:42ZengFrontiers Media S.A.Frontiers in Immunology1664-32242016-12-01710.3389/fimmu.2016.00566225076The selective estrogen receptor modulator raloxifene inhibits neutrophil extracellular trap formation.Roxana Flores0Simon Döhrmann1Christina Schaal2Abdul Hakkim3Victor Nizet4Victor Nizet5Victor Nizet6Ross Corriden7University of California, San DiegoUniversity of California, San DiegoUniversity for Veterinary Medicine HannoverMass General Hospital/Harvard Medical SchoolUniversity of California, San DiegoUniversity of California, San DiegoRady Children's HospitalUniversity of California, San DiegoRaloxifene is a selective estrogen receptor modulator typically prescribed for the prevention/treatment of osteoporosis in postmenopausal women. Although raloxifene is known to have anti-inflammatory properties, its effect on human neutrophils, the primary phagocytic leukocytes of the immune system, remain poorly understood. Here, through a screen of pharmacologically active small molecules, we find that raloxifene prevents neutrophil cell death in response to the classical activator phorbol 12-myristate 13-acetate (PMA), a compound known to induce formation of DNA-based neutrophil extracellular traps (NETs). Inhibition of PMA-induced NET production by raloxifene was confirmed using quantitative and imaging-based assays. Human neutrophils from both male and female donors express the nuclear estrogen receptors ERα and ERβ, known targets of raloxifene. Like raloxifene, selective antagonists of these receptors inhibit PMA-induced NET production. Furthermore, raloxifene inhibited PMA-induced ERK phosphorylation but not reactive oxygen species (ROS) production, pathways known to be key modulators of NET production. Finally, we found that raloxifene inhibited PMA-induced, NET-based killing of the leading human bacterial pathogen, methicillin-resistant Staphylococcus aureus (MRSA). Our results reveal that raloxifene is a potent modulator of neutrophil function and NET production.http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00566/fullHost-Pathogen InteractionsNeutrophilsRaloxifeneMRSAextracellular traps |
| spellingShingle | Roxana Flores Simon Döhrmann Christina Schaal Abdul Hakkim Victor Nizet Victor Nizet Victor Nizet Ross Corriden The selective estrogen receptor modulator raloxifene inhibits neutrophil extracellular trap formation. Frontiers in Immunology Host-Pathogen Interactions Neutrophils Raloxifene MRSA extracellular traps |
| title | The selective estrogen receptor modulator raloxifene inhibits neutrophil extracellular trap formation. |
| title_full | The selective estrogen receptor modulator raloxifene inhibits neutrophil extracellular trap formation. |
| title_fullStr | The selective estrogen receptor modulator raloxifene inhibits neutrophil extracellular trap formation. |
| title_full_unstemmed | The selective estrogen receptor modulator raloxifene inhibits neutrophil extracellular trap formation. |
| title_short | The selective estrogen receptor modulator raloxifene inhibits neutrophil extracellular trap formation. |
| title_sort | selective estrogen receptor modulator raloxifene inhibits neutrophil extracellular trap formation |
| topic | Host-Pathogen Interactions Neutrophils Raloxifene MRSA extracellular traps |
| url | http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00566/full |
| work_keys_str_mv | AT roxanaflores theselectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation AT simondohrmann theselectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation AT christinaschaal theselectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation AT abdulhakkim theselectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation AT victornizet theselectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation AT victornizet theselectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation AT victornizet theselectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation AT rosscorriden theselectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation AT roxanaflores selectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation AT simondohrmann selectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation AT christinaschaal selectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation AT abdulhakkim selectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation AT victornizet selectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation AT victornizet selectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation AT victornizet selectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation AT rosscorriden selectiveestrogenreceptormodulatorraloxifeneinhibitsneutrophilextracellulartrapformation |