On February 25, Valerie Horsley, PhD, from Yale University, presented on her lab’s newest Cell Reports paper, which shows how a common amino acid helps immune cells shift from inflammation to repair.

When skin is cut, the body mounts a furious defence. Immune cells surge into the damaged tissue, blood vessels are disrupted, and nutrients vanish. For a brief window, the wound becomes a biological no man’s land–metabolically starved yet teeming with activity.

Whether that chaos settles into healing or spirals into chronic inflammation, Dr. Valerie Horsley’s team suggests, hinges on something deceptively simple: the availability of the amino acid glutamine.

In this week’s presentation of Tissue Talks, a weekly Wednesday Lecture series hosted by Dr. Gordana Vunjak and the Laboratory for Stem Cells and Tissue Engineering, Horsley presented her lab’s newly published study, led by first author Yiting Xu, a former PhD student in her lab and now a medical student at Northwestern University. The paper, Glutamine metabolism tunes myeloid responses to drive resolution of inflammation during skin repair, explores how metabolism shapes immune-cell behaviour during wound healing.

Repairing tissue is energetically expensive, between the multiplying cells and the newly forming blood vessels. Without a functioning blood supply, nutrients can’t easily reach the site, creating what Horsley calls “a nutrient desert.”

Thus, researchers focused on macrophages, immune cells that coordinate inflammation, within mouse models. On the first day after injury, inflammatory macrophages dominate the wound, recruiting neutrophils to clear debris and pathogens. By day three, those macrophages normally transition into a resolving state, dampening inflammation and supporting tissue rebuilding.

In chronic wounds, including diabetic foot ulcers, that transition fails. Neutrophils persist, inflammation remains high, and the tissue cannot properly repair.

Comparing macrophages from day-one and day-three wounds in mice, the researchers detected a metabolic shift. Genes and metabolites associated with glutamine metabolism were enriched in macrophages that had entered the resolving phase.

To test whether this was causal, the team removed glutamine from either the mouse diet or genetically disabled glutaminase 1, the enzyme immune cells use to process glutamine. While early inflammation looked normal, by day 5, the healing was impaired. The wounds were larger, blood vessel growth was reduced, and rebuilding cells were sparse. Without glutamine metabolism, inflammation persisted, and tissue repair was impaired.

Macrophages lacking glutamine metabolism also continued expressing genes that attract neutrophils, including chemokines in the CCL and CXCL families.  In healthy wounds, those signals are normally reduced as inflammation resolves.

The team found changes not just in gene expression but in chromatin, which is the packaging that controls which genes are accessible. In the absence of glutamine metabolism, chromatin around neutrophil-recruitment genes remained open and active, suggesting that metabolites influence how DNA is read and organized, shaping whether macrophages sustain inflammatory signals or turn them off at the appropriate time. 

In other words, glutamine isn’t simply fuel. Through its downstream metabolic products, it helps regulate the gene programs that guide immune cells from defence to repair.

Although this study focused on glutamine and has not expanded to define the role of glutamine metabolism in human macrophages yet, Horsley emphasized that many other metabolites may influence tissue repair in similar ways. “It suggests that just this amino acid isenough to tune gene expression to modulate the specific function of immune cells to drive this resolution of inflammation,” she said. Exploring how other metabolites shape healing, she added, will be “a fun project for all of us” in the years ahead.

Tissue Talks is a weekly Wednesday lecture series on tissue engineering advancements hosted by Dr. Gordana Vunjak and the Laboratory for Stem Cells and Tissue Engineering. Next week’s speaker is Santiago Correa from Columbia University.

Image via Wikimedia Commons