Inflammatory Molecule Links Metabolic Environment and Innate Immunity Interview with:

David Underhill, PhD Professor of Biomedical Sciences Research scientist, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Cedars-Sinai

Dr. David Underhill

David Underhill, PhD
Professor of Biomedical Sciences
Research scientist, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute
Los Angeles, CA What is the background for this study?

Response: “Innate immunity” is the body’s natural resistance to microbial infection and stands in contrast to “adaptive immunity,” which is the body’s learned response to infection (e.g. antibodies and vaccines). In the standard model of innate immunity that has emerged over the last several decades, scientists have come to understand that the human genome encodes many “receptors” that have evolved as sensors for specific common microbial molecules, such as bacterial or viral DNA or components of bacterial or fungal cell walls. The job of these receptors is to survey the environment (skin, blood, etc.) for potentially dangerous microbes and initiate inflammatory responses if they are found. These activities are essential for defense against infection, and people and animals with defects in these sensors or the responses they trigger can be susceptible to infection.

My laboratory has been interested for more than a decade in identifying these innate sensors and the microbial targets that they recognize. In this study, we were looking for the sensor that allows white blood cells (e.g. macrophages and dendritic cells) to detect Gram-positive bacterial cell walls and trigger a specific inflammatory response: secretion of the potent inflammatory mediator interleukin-1β (IL-1β). What are the main findings?

Response: We came to the unexpected conclusion, based on our data, that the sensor is not a dedicated, purpose-built receptor, but instead is an enzyme in the cell’s glycolytic pathway that is serving double duty. The enzyme, hexokinase 2, mediates the first step in the process by which a cell burns the common sugar glucose to make energy. We found that this enzyme notices a related sugar, N-acetylglucosamine (NAG), that is released from bacterial cell walls after a macrophage eats a Gram-positive bacterium and begins to digest it. When hexokinase 2 detects NAG, it moves to a different location in the cell, and this movement triggers IL-1β secretion.

Since hexokinase is known to move around in the cell based on whether the cell is trying to use glucose or not, we suspected it was possible that changes in cellular metabolism might, under certain circumstances, promote IL-1β secretion. Our study demonstrated that metabolic conditions that provoke hexokinase movement in the cell can indeed drive IL-1β secretion. What should readers take away from your report?

Response: IL-1β is a potent inflammatory protein, and therapeutics that block IL-1β (e.g. anakinra) are being aggressively investigated for treatment of diverse inflammatory diseases, such as rheumatoid arthritis, lupus, type 2 diabetes, familial Mediterranean fever and asbestosis. As such, there is intense interest in understanding how the production of IL-1β is regulated.

The idea that IL-1β production might be linked to the metabolic environment of immune cells is intriguing. Many metabolic diseases (e.g. diabetes, obesity, heart disease) are understood to be associated with chronic inflammation, but where this association comes from and whether it is a cause, effect, or both for these diseases is not fully understood. Our study suggests that in the right circumstances, dysregulated metabolism might be sensed by immune cells as a cause for releasing IL-1β, leading to inflammation. What recommendations do you have for future research as a result of this study?

Response: If we want to manipulate the ability of hexokinase to drive inflammation (for example, to block unwanted inflammation or to promote stronger antimicrobial defense), we need to understand how its movement in a cell can cause IL-1β secretion. Data suggest this movement has something to do with alterations in organelles called mitochondria that act as the “batteries” of a cell. But future studies will have to establish the molecular mechanisms by which these organelles participate in regulating inflammatory signaling. Further, experiments will have to be designed to test whether hexokinase-sensed metabolic changes participate in chronic inflammatory diseases related to metabolism. Thank you for your contribution to the community.


Hexokinase Is an Innate Immune Receptor for the Detection of Bacterial Peptidoglycan
Wolf, Andrea J. et al.
Cell , Volume 166 , Issue 3 , 624 – 636

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Last Updated on September 7, 2016 by Marie Benz MD FAAD