Recognition of microbial infection by the innate immune system results in acute inflammatory responses that help to eliminate the invading pathogens. Innate immunity is also critical for initiating and shaping adaptive immune responses of T and B cells by inducing the activation and maturation of antigen-presenting cells (APC). However, a prolonged inflammatory response, although beneficial to promoting adaptive immunity, could be dangerous to the host by causing overt inflammation and tissue damage. Thus, both functions of the innate immune system must be properly regulated to deliver an effective, antigen-specific response to pathogens while simultaneously containing and limiting potential damage to the host. The mechanisms that control the balance between acute inflammation and adaptive responses are poorly understood. While pathogen recognition begins at the receptor level, it is the signaling components downstream of each receptor and the way they interact with each other that ultimately determine the specific transcriptional response and immunological outcome. Among the central pathways activated by innate signals are the MAP kinases (MAPK). MAPK, comprised of ERK, JNK and p38, are a family of serine/threonine kinases that play prominent roles in the immune system. Prolonged activation of MAPK is attenuated through the action of MAPK phosphatases (MKP). MKP-1, a prototypical member of this phosphatase family that inactivates p38 and JNK, has emerged as a key regulator of innate immune responses by limiting excessive cytokine production in response to Toll-like receptor (TLR) stimulation. Surprisingly, whereas MKP-1-deficient mice exhibited elevated responses to acute inflammation and bacterial infection, TLR-induced activation of adaptive immunity was substantially suppressed. Consistent with a pleiotropic function of MKP-1, MKP-1 controls the expression of both pro- and anti-inflammatory components and transcription factors in TLR-stimulated cells. Our central hypothesis is that the two functions of the innate immune system, acute inflammation and induction of adaptive immunity, are coordinately regulated by a distinct pathway mediated by MKP-1 and its downstream p38 signaling and effector molecules. To test this hypothesis, we intend to address the following three specific questions: 1. How is the balance between TLR-induced acute inflammation and adaptive immunity controlled? 2. Which signaling pathway mediates the function of MKP-1 in TLR signaling? 3. How does transient induction of MKP-1 impose a sustained effect on gene expression and immune responses? Our studies promise to provide new insight into the pathways that bridge innate and adaptive immunity.

Public Health Relevance

Recognition of microbial infection by the innate immune system results in acute inflammatory responses that help to eliminate the invading pathogens, and the initiation of adaptive immunity that provides antigen-specific protection. Dysregulation of the crosstalk between innate and adaptive immunity can lead to immunodeficiency and inflammatory and autoimmune diseases. Therefore, a better understanding of the molecules and mechanisms that regulate immune function is essential for future efforts to prevent and treat these immune- mediated diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064599-05
Application #
8271382
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Utz, Ursula
Project Start
2008-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$360,150
Indirect Cost
$145,775
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Zeng, Hu; Chi, Hongbo (2015) Metabolic control of regulatory T cell development and function. Trends Immunol 36:12-Mar
Wei, Jun; Yang, Kai; Chi, Hongbo (2014) Cutting edge: Discrete functions of mTOR signaling in invariant NKT cell development and NKT17 fate decision. J Immunol 193:4297-301
Mahmud, Shawn A; Manlove, Luke S; Schmitz, Heather M et al. (2014) Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat Immunol 15:473-81
Karmaus, Peer W F; Chi, Hongbo (2014) Genetic dissection of dendritic cell homeostasis and function: lessons from cell type-specific gene ablation. Cell Mol Life Sci 71:1893-906
Shrestha, Sharad; Yang, Kai; Wei, Jun et al. (2014) Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs. Proc Natl Acad Sci U S A 111:14858-63
Yang, Kai; Shrestha, Sharad; Zeng, Hu et al. (2013) T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity 39:1043-56
Zeng, Hu; Chi, Hongbo (2013) mTOR and lymphocyte metabolism. Curr Opin Immunol 25:347-55
Shi, Lewis Zhichang; Kalupahana, Nishan S; Turnis, Meghan E et al. (2013) Inhibitory role of the transcription repressor Gfi1 in the generation of thymus-derived regulatory T cells. Proc Natl Acad Sci U S A 110:E3198-205
Zeng, Hu; Yang, Kai; Cloer, Caryn et al. (2013) mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499:485-90
Huang, Gonghua; Wang, Yanyan; Chi, Hongbo (2013) Control of T cell fates and immune tolerance by p38* signaling in mucosal CD103+ dendritic cells. J Immunol 191:650-9

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