Loss of Jak2 Selectively Suppresses DC-Mediated Innate Immune Response and Protects Mice from Lethal Dose of LPS-Induced Septic Shock Jixin Zhong1,2, Ping Yang2,3, Kenjiro Muta4, Robert Dong 2 , Mario Marrero4, Feili Gong1*, Cong-Yi 2 Wang * 1 Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China, 2 Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta, Georgia, United States of America, 3 Center for Biomedical Research, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China, 4 Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States of America 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+/+Jak2fl/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. Jak22/2 DCs were less potent in response to inflammatory stimuli and showed reduced capacity to secrete proinflammatory cytokines such as TNFa and IL-12. As a result, Jak22/2 mice were defective for the early clearance of Listeria after infection. However, their potency to mediate adaptive immune response was not affected. Unlike DCs, Jak22/2 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, Jak22/2 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: Zhong J, Yang P, Muta K, Dong R, Marrero M, et al. (2010) Loss of Jak2 Selectively Suppresses DC-Mediated Innate Immune Response and Protects Mice from Lethal Dose of LPS-Induced Septic Shock. PLoS ONE 5(3): e9593. doi:10.1371/journal.pone.0009593 Editor: Maciej Lesniak, The University of Chicago, United States of America Received November 13, 2009; Accepted February 16, 2010; Published March 9, 2010 Copyright: 2010 Zhong et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Juvenile Diabetes Research Foundation (JDRF, 1-2007-181 and 1-2007-192) and NIH/NIDDK (DK074957) to CYW, and supported in part by the National Key Basic Research Program of China (2007CB512402) to FG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: flgong@163.com (FG); cwang@mcg.edu (C-YW) Introduction Dendritic cells (DCs) are the most potent antigen presenting cells (APCs) known today [1]. Other than their well-recognized role in mediating adaptive immune response, they also serve as a key component of innate immunity and bridge innate and adaptive immune response to bacteria and other pathogens [2– 4]. The pathogen associated molecular patterns (PAMPs) or damage associated molecular patterns (DAMPs) are first sensed by pathogen recognition receptors (PRRs) expressed on their surface, followed by initiating a serial prompt responses such as endocytosis and cytokine secretion. Immune disorders are a system out of balance as manifested by either excessive or defective response, and septic shock is a typical example caused by the excessive innate immune response [5–10]. Septic shock (or endotoxic shock) is a severe sepsis with organ hypoperfusion and hypotension that are poorly responsive to initial fluid resuscitation. The mortality rate in patients with septic shock ranges from 20 to 80%, and in the USA alone it is estimated that more than 100,000 deaths occur each year [11,12]. Therefore, septic shock has been accounted for the most common cause of death in the intensive care unit [13–15]. Given the importance of DCs in the vanguard of innate immune response, research into the development of new septic therapeutics has focused more and more on their crucial role in orchestrating the initial host response to infection [16], but the advancement has been painfully slow and fraught with difficulties. The ideal therapeutic target for septic shock would be directed to selectively modulate innate immune response without affecting adaptive defense. Nevertheless, it would be a formidable challenge to characterize such a target among all immune regulatory molecules within the genome. Jak2 is one of the four janus kinase members identified in mammals [17,18]. It acts as a critical component of signal pathways involved in cellular survival, proliferation, differentiation and apoptosis [19–21]. Particularly, Jak2 has been suggested to be crucial for the regulation of DC development and functionality [22–25]. However, the exact function for Jak2 in DCs remained, somehow, controversial depending on each particular chemical inhibitor used. In the present study, we induced Jak2 deficiency in adult mice by crossing Jak2fl/fl mice with Cre-ERT2 transgenic mice. Loss of Jak2 only selectively suppresses the capacity of DCs to initiate innate immune response, but there is no discernable PLoS ONE | www.plosone.org 1 March 2010 | Volume 5 | Issue 3 | e9593