Loss of Jak2 selectively suppresses DC-mediated innate immune response and protects mice from lethal dose of LPS-induced septic shock.

Hdl Handle:
http://hdl.handle.net/10675.2/21
Title:
Loss of Jak2 selectively suppresses DC-mediated innate immune response and protects mice from lethal dose of LPS-induced septic shock.
Authors:
Zhong, Jixin; Yang, Ping; Muta, Kenjiro; Dong, Robert; Marrero, Mario; Gong, Feili; Wang, Cong-Yi
Abstract:
Given the importance of Jak2 in cell signaling, a critical role for Jak2 in immune cells especially dendritic cells (DCs) has long been proposed. The exact function for Jak2 in DCs, however, remained poorly understood as Jak2 deficiency leads to embryonic lethality. Here we established Jak2 deficiency in adult Cre(+/+)Jak2(fl/fl) mice by tamoxifen induction. Loss of Jak2 significantly impaired DC development as manifested by reduced BMDC yield, smaller spleen size and reduced percentage of DCs in total splenocytes. Jak2 was also crucial for the capacity of DCs to mediate innate immune response. Jak2(-/-) DCs were less potent in response to inflammatory stimuli and showed reduced capacity to secrete proinflammatory cytokines such as TNFalpha and IL-12. As a result, Jak2(-/-) mice were defective for the early clearance of Listeria after infection. However, their potency to mediate adaptive immune response was not affected. Unlike DCs, Jak2(-/-) macrophages showed similar capacity secretion of proinflammatory cytokines, suggesting that Jak2 selectively modulates innate immune response in a DC-dependent manner. Consistent with these results, Jak2(-/-) mice were remarkably resistant to lethal dose of LPS-induced septic shock, a deadly sepsis characterized by the excessive innate immune response, and adoptive transfer of normal DCs restored their susceptibility to LPS-induced septic shock. Mechanistic studies revealed that Jak2/SATA5 signaling is pivotal for DC development and maturation, while the capacity for DCs secretion of proinflammatory cytokines is regulated by both Jak2/STAT5 and Jak2/STAT6 signaling.
Citation:
PLoS One. 2010 Mar 9; 5(3):e9593
Issue Date:
16-Mar-2010
URI:
http://hdl.handle.net/10675.2/21
DOI:
10.1371/journal.pone.0009593
PubMed ID:
20231889
PubMed Central ID:
PMC2834745
Type:
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
ISSN:
1932-6203
Appears in Collections:
Center for Biotechnology and Genomic Medicine: Faculty Research and Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorZhong, Jixinen_US
dc.contributor.authorYang, Pingen_US
dc.contributor.authorMuta, Kenjiroen_US
dc.contributor.authorDong, Roberten_US
dc.contributor.authorMarrero, Marioen_US
dc.contributor.authorGong, Feilien_US
dc.contributor.authorWang, Cong-Yien_US
dc.date.accessioned2010-09-24T20:59:21Z-
dc.date.available2010-09-24T20:59:21Z-
dc.date.issued2010-03-16en_US
dc.identifier.citationPLoS One. 2010 Mar 9; 5(3):e9593en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid20231889en_US
dc.identifier.doi10.1371/journal.pone.0009593en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/21-
dc.description.abstractGiven the importance of Jak2 in cell signaling, a critical role for Jak2 in immune cells especially dendritic cells (DCs) has long been proposed. The exact function for Jak2 in DCs, however, remained poorly understood as Jak2 deficiency leads to embryonic lethality. Here we established Jak2 deficiency in adult Cre(+/+)Jak2(fl/fl) mice by tamoxifen induction. Loss of Jak2 significantly impaired DC development as manifested by reduced BMDC yield, smaller spleen size and reduced percentage of DCs in total splenocytes. Jak2 was also crucial for the capacity of DCs to mediate innate immune response. Jak2(-/-) DCs were less potent in response to inflammatory stimuli and showed reduced capacity to secrete proinflammatory cytokines such as TNFalpha and IL-12. As a result, Jak2(-/-) mice were defective for the early clearance of Listeria after infection. However, their potency to mediate adaptive immune response was not affected. Unlike DCs, Jak2(-/-) macrophages showed similar capacity secretion of proinflammatory cytokines, suggesting that Jak2 selectively modulates innate immune response in a DC-dependent manner. Consistent with these results, Jak2(-/-) mice were remarkably resistant to lethal dose of LPS-induced septic shock, a deadly sepsis characterized by the excessive innate immune response, and adoptive transfer of normal DCs restored their susceptibility to LPS-induced septic shock. Mechanistic studies revealed that Jak2/SATA5 signaling is pivotal for DC development and maturation, while the capacity for DCs secretion of proinflammatory cytokines is regulated by both Jak2/STAT5 and Jak2/STAT6 signaling.en_US
dc.rightsThe PMC Open Access Subset is a relatively small part of the total collection of articles in PMC. Articles in the PMC Open Access Subset are still protected by copyright, but are made available under a Creative Commons or similar license that generally allows more liberal redistribution and reuse than a traditional copyrighted work. Please refer to the license statement in each article for specific terms of use. The license terms are not identical for all articles in this subset.en_US
dc.titleLoss of Jak2 selectively suppresses DC-mediated innate immune response and protects mice from lethal dose of LPS-induced septic shock.en_US
dc.typeJournal Articleen_US
dc.typeResearch Support, N.I.H., Extramuralen_US
dc.typeResearch Support, Non-U.S. Gov'ten_US
dc.identifier.pmcidPMC2834745en_US
dc.contributor.corporatenameCenter for Biotechnology and Genomic Medicineen_US
dc.contributor.corporatenameVascular Biology Centeren_US

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