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 #
5R01NS064599-04
Application #
8096541
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Utz, Ursula
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$360,150
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Tan, Haiyan; Yang, Kai; Li, Yuxin et al. (2017) Integrative Proteomics and Phosphoproteomics Profiling Reveals Dynamic Signaling Networks and Bioenergetics Pathways Underlying T Cell Activation. Immunity 46:488-503
Shi, Lewis Zhichang; Saravia, Jordy; Zeng, Hu et al. (2017) Gfi1-Foxo1 axis controls the fidelity of effector gene expression and developmental maturation of thymocytes. Proc Natl Acad Sci U S A 114:E67-E74
Zeng, Hu; Chi, Hongbo (2017) mTOR signaling in the differentiation and function of regulatory and effector T cells. Curr Opin Immunol 46:103-111
Karmaus, Peer W F; Herrada, Andrés A; Guy, Cliff et al. (2017) Critical roles of mTORC1 signaling and metabolic reprogramming for M-CSF-mediated myelopoiesis. J Exp Med 214:2629-2647
Zeng, Hu; Cohen, Sivan; Guy, Cliff et al. (2016) mTORC1 and mTORC2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation. Immunity 45:540-554
Wei, Jun; Long, Lingyun; Yang, Kai et al. (2016) Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat Immunol 17:277-85
Huang, Gonghua; Wang, Yanyan; Vogel, Peter et al. (2015) Control of IL-17 receptor signaling and tissue inflammation by the p38?-MKP-1 signaling axis in a mouse model of multiple sclerosis. Sci Signal 8:ra24
Liu, Chaohong; Chapman, Nicole M; Karmaus, Peer W F et al. (2015) mTOR and metabolic regulation of conventional and regulatory T cells. J Leukoc Biol 97:837-847
Shrestha, Sharad; Yang, Kai; Guy, Cliff et al. (2015) Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol 16:178-87
Zeng, Hu; Chi, Hongbo (2015) Metabolic control of regulatory T cell development and function. Trends Immunol 36:3-12

Showing the most recent 10 out of 37 publications