Obesity is a crucial public health problem that is associated with low-grade systemic inflammation and cardiovascular disease, affecting 25% of the population and its incidence is growing. IL-1R/TLRs have been directly implicated in obesity-associated inflammatory diseases. TLR2 or TLR4 deficiency reduced diet-induced insulin resistance and atherosclerosis, while human TLR4 null mutations are associated with reduced risk of atherosclerosis. The overall objective of this proposal is to elucidate IL-1R/TLR-mediated signaling mechanisms in the inflammatory response associated with metabolic diseases. Our long-term goals are to identify new therapeutic targets and to develop more effective anti-inflammatory small molecule drugs. Genetic and biochemical studies by us and others revealed that IL- 1R/TLRs interact with the adaptor MyD88 to initiate TAK1 (TGF?-activated kinase 1)- and MEKK3 (MAP kinase kinase kinase 3)-dependent pathways. Each pathway involves cascades of kinases organized by multiple adapter molecules into parallel and sequential signaling complexes, leading to activation of the transcription factor NF?B. IL- 1R/TLRs also mediate mRNA stabilization and promote protein translation of cytokines and chemokines through their impact on RNA binding proteins and translation mediators (mTOR and MnK1). We have previously shown that the kinase activity of IRAK4 (IL-1 receptor-associated kinase) is required for TAK1-dependent NF?B activation and posttranscriptional induction of cytokines and chemokines, but not for MEKK3-dependent NF?B activation. We have recently reported that while IRAK1 and IRAK2 interact with MyD88-IRAK4 to mediate TAK1-dependent NF?B activation and posttranscriptional control respectively; IRAKM (without functional kinase domain) mediates a second wave of IL-1R-TLR-induced NF?B activation through the MEKK3-dependent pathway, but also attenuates protein translation of cytokines and chemokines. In this proposal, we propose two Aims.
In Aim 1, we will elucidate the molecular mechanism of IL-1R/TLRs signaling: (1) Delineate the precise molecular mechanism for IRAK1-mediated TAK1-dependent NF?B activation; (2) Investigate the mechanisms of IRAK2-mediated posttranscriptional control of cytokines and chemokines; (3) Elucidate the mechanisms by which IRAKM mediates MEKK3-dependent NF?B activation and its inhibitory effect on translational control of cytokines and chemokines.
In Aim 2, we will investigate the mechanism of IL-1R/TLRs signaling for the development of obesity-associated diseases: (1) Study how IL- 1R/TLRs signaling mediate the cross-talk between adipocytes and macrophages contributing to diet-induced systemic inflammation and exacerbation on atherosclerosis; (2) Determine the impact of IL-1R/TLRs signaling in endothelial cells on the recruitment of monocytes and polarization of inflammatory macrophages.

Public Health Relevance

Project 1 (P1). Project Narrative Our proposed study will provide novel mechanistic insights into IL-1R/TLR-mediated inflammatory response, initiation and pathogenesis of obesity-associated inflammatory diseases. The elucidation of the detailed signaling mechanisms will not only establish the molecular basis for future anti-inflammatory drug design and development of new therapies for metabolic diseases, but will also advance our knowledge about innate immune signal transduction in general.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Hasan, Ahmed a K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
United States
Zip Code
Herjan, Tomasz; Hong, Lingzi; Bubenik, Jodi et al. (2018) IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling. Nat Immunol 19:354-365
Robinet, Peggy; Milewicz, Dianna M; Cassis, Lisa A et al. (2018) Consideration of Sex Differences in Design and Reporting of Experimental Arterial Pathology Studies-Statement From ATVB Council. Arterioscler Thromb Vasc Biol 38:292-303
Zhang, Cun-Jin; Wang, Chenhui; Jiang, Meiling et al. (2018) Act1 is a negative regulator in T and B cells via direct inhibition of STAT3. Nat Commun 9:2745
Han, Juying; Enyindah-Asonye, Gospel; Lin, Feng et al. (2018) CD6 expression has no effect on atherosclerosis in apolipoprotein E-deficient mice. BMC Res Notes 11:229
Sarvestani, Samaneh K; Signs, Steven A; Lefebvre, Veronique et al. (2018) Cancer-predicting transcriptomic and epigenetic signatures revealed for ulcerative colitis in patient-derived epithelial organoids. Oncotarget 9:28717-28730
Arif, Abul; Yao, Peng; Terenzi, Fulvia et al. (2018) The GAIT translational control system. Wiley Interdiscip Rev RNA 9:
Hai, Qimin; Ritchey, Brian; Robinet, Peggy et al. (2018) Quantitative Trait Locus Mapping of Macrophage Cholesterol Metabolism and CRISPR/Cas9 Editing Implicate an ACAT1 Truncation as a Causal Modifier Variant. Arterioscler Thromb Vasc Biol 38:83-91
Eswarappa, Sandeep M; Potdar, Alka A; Sahoo, Sarthak et al. (2018) Metabolic origin of the fused aminoacyl-tRNA synthetase, glutamyl-prolyl-tRNA synthetase. J Biol Chem 293:19148-19156
Halawani, Dalia; Gogonea, Valentin; DiDonato, Joseph A et al. (2018) Structural control of caspase-generated glutamyl-tRNA synthetase by appended noncatalytic WHEP domains. J Biol Chem 293:8843-8860
Zhou, Hao; Bulek, Katarzyna; Li, Xiao et al. (2017) IRAK2 directs stimulus-dependent nuclear export of inflammatory mRNAs. Elife 6:

Showing the most recent 10 out of 276 publications