Joel Schilling, M.D., Ph.D.

Assistant Professor
Internal Medicine
Cardiovascular
Pathology and Immunology

Immunology Program

  • 314-747-8499

  • 8086

  • 10306 BJC-IH

  • jschilli@dom.wustl.edu

  • http://schillinglab.wustl.edu/

  • macrophages, tissue injury, infection, diabetes, heart failure, myocardial infarction, toll like receptors

  • My research is focused on defining the role(s) of Toll-like Receptor mediated inflammation in heart failure associated with diabetes and obesity

Research Abstract:

Macrophages are innate immune cells that play a crucial role in the host response to tissue injury and infection. The activation of macrophages by these "danger signals" occurs largely via toll-like receptor (TLR) signaling. Diabetes and metabolic syndrome are common metabolic diseases associated with abnormalities in inflammatory signaling, innate host defenses, and tissue repair. The inflammatory/healing defect in diabetics manifests as excessive morbidity and mortality related to cardiovascular and infectious disease complications. Until recently it was thought that hyperglycemia was the predominant cause of organ injury in diabetes. However, recent data that aggressive glucose control does not improve diabetic complications has called this assumption into question. In addition to elevated blood glucose, diabetes is also associated with increased levels of serum and tissue triglycerides (TAG) and free fatty acids (FFA), particularly saturated fatty acids (SFAs). In many cell types, excess SFAs cause endoplasmic reticulum stress, reactive oxygen species generation, and ultimately cell death. My preliminary studies demonstrate that whereas palmitate or the classical TLR4 agonist, bacterial lipopolysaccharide (LPS) alone do not cause cytotoxicity, the combination of these stimuli trigger a profound death response in macrophages. These findings suggest that dyslipidemia may contribute to abnormal tissue healing and infection clearance in diabetics by altering macrophage survival and cytokine responses following TLR activation. My future research will focus on investigating the mechanism(s) of crosstalk between SFAs and TLRs and determining the contribution of this phenomenon to cardiovascular and infectious complications in diabetes. This research has the potential to identify novel inflammatory targets for the prevention of diabetic complications.
The goals of our lab are:
1) To elucidate the molecular mechanisms of crosstalk between TLR4-signaling and SFA in regulating macrophage survival and cytokine responses. Our preliminary data demonstrates that the SFA palmitate dramatically alters macrophage survival and cytokine responses following TLR4 activation. Dissecting the mechanism by which SFAs alter TLR4 signaling in macrophages could lead to the discovery of novel therapeutic targets. To achieve this objective we will focus on the intersection between inflammatory signaling and membrane remodeling. A combination of genetic loss of function, inhibitors, and lipidomics will be used to dissect the key molecules involved in crosstalk between SFA and TLR4.

2) To investigate the impact of SFA on TLR4-mediated myocardial inflammatory responses during myocardial injury/infarction and pressure overload stress. Diabetics are known to have dysfunctional myocardial healing after ischemia/infarction that leads to an increase in myocyte cell death and heart failure. TLR4 is involved in the myocardial inflammatory response to tissue injury. This aim will test the hypothesis that macrophage responses are crucial for appropriate infarct healing and that macrophage dysfunction in diabetic animals contributes to worse outcomes following MI. To investigate this hypothesis I will use in vitro and in vivo approaches to assess the impact of lipid overload on macrophage and myocyte responses to injury.

3) To determine the relevance of SFA on TLR-mediated macrophage responses in infection. The importance of macrophages in the host response to infection suggests that lipid-induced dysfunction in these cells could increase host susceptibility to diverse pathogens. We are interested in exploring how dyslipidemia influences infection pathogenesis.

Selected Publications:

He L, Weber KJ, Diwan A, and Schilling JD. Inhibition of mTOR reduces lipotoxic cell death in primary macrophages through an autophagy-independent mechanism. J Leuk Biol. 2016 June. PMCID: 27312848

Schilling JD. Dousing fire with gasoline: interplay between lysosome damage and the NLRP3 inflammasome. Am J Physiol Cell Physiol. 2016. Jun; PMCID: 27306368

He L, Weber KJ, and Schilling JD. Glutamine Modulates Macrophage Lipotoxicity. Nutrients. 2016. Apr;12 (4). PCMID: 27077881

Schilling JD. The Mitochondria in Diabetic Heart Failure: from pathogenesis to therapeutic promise. Antioxid Redox Signal. 2015. PCMID: 25761843

Symington JW, Wang C, Twentyman J, Owusu-Boaitey N, Schwendener R, Nunez G, Schilling JD, and Mysorekar IU. ATG16L1 deficiency in macrophages drives clearance of uropathogenic E. coli in an IL-1beta- dependent manner. Mucosal Immunol. 2015. Feb 11. PMCID: 25669147

Lavine KJ, Epelman S, Uchida K, Weber KJ, Nichols CG, Schilling JD, Ornitz DM, Randolph GJ, Mann DL. Distinct Macrophage Lineages Contribute to Disparate Patterns of Cardiac Recovery and Remodeling in the Neonatal and Adult Heart. PNAS. 2014.
Nov. 11;111(45):16029-34. PMCID 25349429

Weber K and Schilling JD. The Lysosome Mediates Metabolic-Inflammatory Crosstalk in Primary Macrophages. J. Biol Chem. 2014. March 28; 289(13):9158-71. PMCID: 24532802

Schilling JD, Machkovech H, He L, Sidhu R, Fujiwara H, Weber K, Ory DS, and Schaffer, JE. Palmitate and LPS trigger Synergistic Ceramide Production in Primary Macrophages. J Biol Chem. 2013. 2013 Feb 1;288(5):2923-32. PCMID: 23250746

Schilling JD, Machkovech H, He L, Diwan A, Schaffer JE. TLR4 Activation Under Lipotoxic Conditions Leads to Synergistic Macrophage Cell Death Through a TRIF-Dependent Pathway. J Immunol. 2013. Feb;190(3). PCMID: 23275600

Schilling JD, Machkovech H, Kim A, Schwendener, R, and Schaffer JE. Macrophages Modulate Cardiac Function in Lipotoxic Cardiomyopathy. Am J Physiolo Heart Circ Physiol. 2012. Dec;303(11):H1366-73. PCMID: 23042950.

Schilling JD, Lai L, Sambandam, N, Dey C, Leone TL, and Kelly DP. Toll-like Receptor-Mediated Inflammatory Signaling Reprograms Cardiac Energy Metabolism by Repressing Peroxisome Proliferatoractivated receptor g Coactivator-1 (PGC-1) Signaling. Circ Heart Fail 2011 4(4):474-482. PMCID: PMC3144030.

Last Updated: 8/31/2016 9:15:30 AM

Back To Top

Follow us: