Abstract
Incorporation of locally produced signaling molecules into cell-derived vesicles may serve as an endogenous mediator delivery system. We recently reported that levels alpha-2-macroglobulin (A2MG)-containing microparticles are elevated in plasma from patients with sepsis. Herein, we investigated the immunomodulatory actions of A2MG containing microparticles during sepsis. Administration of A2MG-enriched (A2MG-E)-microparticles to mice with microbial sepsis protected against hypothermia, reduced bacterial titers, elevated immunoresolvent lipid mediator levels in inflammatory exudates and reduced systemic inflammation. A2MG-E microparticles also enhanced survival in murine sepsis, an action lost in mice transfected with siRNA for LRP1, a putative A2MG receptor. In vitro, A2MG was functionally transferred onto endothelial cell plasma membranes from microparticles, augmenting neutrophil-endothelial adhesion. A2MG also modulated human leukocyte responses: enhanced bacterial phagocytosis, reactive oxygen species production, cathelicidin release, prevented endotoxin induced CXCR2 downregulation and preserved neutrophil chemotaxis in the presence of LPS. A significant association was also found between elevated plasma levels of A2MG-containing microparticles and survival in human sepsis patients. Taken together, these results identify A2MG enrichment in microparticles as an important host protective mechanism in sepsis.
| Original language | English |
|---|---|
| Pages (from-to) | 27-42 |
| Number of pages | 16 |
| Journal | EMBO Molecular Medicine |
| Volume | 6 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 2014 |
| Externally published | Yes |
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Keywords
- Activation
- Innate immunity
- Lipoprotein receptor-related protein 1
- Neutrophil
- Phagocytosis
ASJC Scopus subject areas
- Molecular Medicine
Cite this
Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis. / Dalli, Jesmond; Norling, Lucy V.; Montero-Melendez, Trinidad; Canova, Donata Federici; Lashin, Hazem; Pavlov, Anton M.; Sukhorukov, Gleb B.; Hinds, Charles J.; Perretti, Mauro.
In: EMBO Molecular Medicine, Vol. 6, No. 1, 01.2014, p. 27-42.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis
AU - Dalli, Jesmond
AU - Norling, Lucy V.
AU - Montero-Melendez, Trinidad
AU - Canova, Donata Federici
AU - Lashin, Hazem
AU - Pavlov, Anton M.
AU - Sukhorukov, Gleb B.
AU - Hinds, Charles J.
AU - Perretti, Mauro
PY - 2014/1
Y1 - 2014/1
N2 - Incorporation of locally produced signaling molecules into cell-derived vesicles may serve as an endogenous mediator delivery system. We recently reported that levels alpha-2-macroglobulin (A2MG)-containing microparticles are elevated in plasma from patients with sepsis. Herein, we investigated the immunomodulatory actions of A2MG containing microparticles during sepsis. Administration of A2MG-enriched (A2MG-E)-microparticles to mice with microbial sepsis protected against hypothermia, reduced bacterial titers, elevated immunoresolvent lipid mediator levels in inflammatory exudates and reduced systemic inflammation. A2MG-E microparticles also enhanced survival in murine sepsis, an action lost in mice transfected with siRNA for LRP1, a putative A2MG receptor. In vitro, A2MG was functionally transferred onto endothelial cell plasma membranes from microparticles, augmenting neutrophil-endothelial adhesion. A2MG also modulated human leukocyte responses: enhanced bacterial phagocytosis, reactive oxygen species production, cathelicidin release, prevented endotoxin induced CXCR2 downregulation and preserved neutrophil chemotaxis in the presence of LPS. A significant association was also found between elevated plasma levels of A2MG-containing microparticles and survival in human sepsis patients. Taken together, these results identify A2MG enrichment in microparticles as an important host protective mechanism in sepsis.
AB - Incorporation of locally produced signaling molecules into cell-derived vesicles may serve as an endogenous mediator delivery system. We recently reported that levels alpha-2-macroglobulin (A2MG)-containing microparticles are elevated in plasma from patients with sepsis. Herein, we investigated the immunomodulatory actions of A2MG containing microparticles during sepsis. Administration of A2MG-enriched (A2MG-E)-microparticles to mice with microbial sepsis protected against hypothermia, reduced bacterial titers, elevated immunoresolvent lipid mediator levels in inflammatory exudates and reduced systemic inflammation. A2MG-E microparticles also enhanced survival in murine sepsis, an action lost in mice transfected with siRNA for LRP1, a putative A2MG receptor. In vitro, A2MG was functionally transferred onto endothelial cell plasma membranes from microparticles, augmenting neutrophil-endothelial adhesion. A2MG also modulated human leukocyte responses: enhanced bacterial phagocytosis, reactive oxygen species production, cathelicidin release, prevented endotoxin induced CXCR2 downregulation and preserved neutrophil chemotaxis in the presence of LPS. A significant association was also found between elevated plasma levels of A2MG-containing microparticles and survival in human sepsis patients. Taken together, these results identify A2MG enrichment in microparticles as an important host protective mechanism in sepsis.
KW - Activation
KW - Innate immunity
KW - Lipoprotein receptor-related protein 1
KW - Neutrophil
KW - Phagocytosis
UR - http://www.scopus.com/inward/record.url?scp=84891948860&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84891948860&partnerID=8YFLogxK
U2 - 10.1002/emmm.201303503
DO - 10.1002/emmm.201303503
M3 - Article
C2 - 24357647
AN - SCOPUS:84891948860
VL - 6
SP - 27
EP - 42
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 1
ER -