image: Resident macrophages (red cells) in the brain, known as microglia, which are critical for maintaining tissue health.
Credit: Pianpian Lin, Ph.D.
A new study led by researchers at the Johns Hopkins Kimmel Cancer Center, its Bloomberg~Kimmel Institute for Cancer Immunotherapy and the Johns Hopkins Bloomberg School of Public Health found that an enzyme involved in protein translation is essential for circulating immune cells, called monocytes, to mature into tissue-resident macrophages, a specialized population of immune cells that maintain organ health by clearing dead cells and debris. Without this enzyme, monocytes enter tissues but fail to fully differentiate, leading to impaired tissue maintenance and persistent immune cell infiltration that causes inflammation instead of repair.
The research, funded in part by the National Institutes of Health and published Jan. 21 in Nature, showed that deoxyhypusine synthase (DHPS) is required for both the differentiation and long-term survival of macrophages across multiple organs, including the lung, liver, brain, kidney, heart and peritoneal cavity.
Using a series of mouse models, the investigators, led by Erika Pearce, Ph.D., Bloomberg Distinguished Professor in the Department of Oncology and the Department of Biochemistry and Molecular Biology, demonstrated that DHPS controls a core, tissue-agnostic program that enables macrophages to adhere to their local environment, interact with surrounding cells and carry out the essential functions that maintain tissue balance and organ health.
“Tissue resident macrophages are critical for tissue homeostasis, such as clearing out dead cells, repairing damage and maintaining balance in organs,” says Pearce. “When these cells can’t mature properly, these protective functions are lost, contributing to inflammation and disease.”
Tissue-resident macrophages form during embryonic development and typically self-renew locally. However, during injury or cell loss, bone-marrow-derived monocytes are recruited into tissues and must differentiate into mature macrophages to restore the normal, healthy population of macrophages. The study found that when DHPS was deleted in myeloid cells, macrophages were present in tissues but lacked the defining features and functions of mature tissue-resident macrophages.
Although monocytes were able to migrate into tissues and begin the differentiation process, without DHPS, they were unable to complete the transition to fully functional tissue-resident macrophages. As a result, tissue and organs experienced an ongoing influx of immature immune cells that failed to restore normal macrophage populations.
“The monocyte migration/infiltration was persistent but, ultimately, futile,” explains Gustavo Carrizo, Ph.D., a former graduate student in the Pearce lab and first author on the study. “They could enter tissues, but without DHPS they couldn’t become the right kind of macrophage needed to maintain and repair those tissues.”
The researchers traced these defects to the polyamine–hypusine pathway. Analyses of gene activity, protein production and protein-making machinery revealed that DHPS is required for efficient translation of a subset of genes involved in cell adhesion (the ability to stick to their surroundings and to other cells so they can stay in the correct place and function properly), signaling, and tissue interaction. Without DHPS, macrophages failed to express key proteins needed to anchor themselves within tissues and respond appropriately to local cues.
Imaging studies showed that DHPS-deficient macrophages had abnormal shape and positioning within tissues, while functional assays demonstrated defects in the clearance of dead cells and tissue maintenance. In the lung, this impairment led to accumulation of surfactant material, a substance in the lungs that keeps air sacs open, and immune cell infiltration, while in the liver, acute macrophage depletion followed by failed restoration resulted in vascular disruption and tissue damage.
“Because tissue-resident macrophages play roles in cancer, wound healing, fibrosis and inflammatory diseases, this pathway could be relevant across a wide range of diseases, as well as in aging, where inflammation and impaired tissue repair are common,” says Daniel Puleston, Ph.D., assistant professor of immunology and immunotherapy at the Icahn School of Medicine at Mount Sinai and a co-senior author on the paper.
Together, the findings identify DHPS as a central, cell-intrinsic regulator of macrophage maturation that operates independently of tissue type. By linking metabolic control of protein translation to immune cell differentiation and tissue stability, the study provides a unifying mechanism for how monocytes become long-living, functional tissue-resident macrophages.
The authors note that understanding this pathway has implications for aging, inflammatory disease and therapies that aim to target macrophages across tissues, where restoring or modulating macrophage function could influence long-term tissue health. Next steps, they say, will focus on identifying the full set of DHPS-dependent proteins and determining how this pathway influences macrophage behavior in specific diseases, where promoting tissue repair or limiting inflammation may require different therapies.
“This is a very fundamental pathway for these cells,” Pearce says. “Understanding when and where macrophages depend on this process, and when it might be beneficial to enhance or inhibit, is an important next step.”
In addition to Carrizo, Puleston and Pearce, other researchers participating in the study are Pianpian Lin, Seung Hyun Lee, Kevin Shenderov, Camille Blerlot, Minsun Cha, Lena Schimmelpfennig, Zhen Shen, Nikki van Teijlingen Bakker, Katarzyna Grzes, Beth Kelly, Niloufar Safinia, Kate Schole, Yaarub Musa, Gerhard Mittler, Yoh Zen, Edward Pearce, Florent Ginhoux and David Sanin.
The research was supported by Bloomberg Philanthropies and the National Institutes of Health grants AI170599 and AI177282.
The researchers report the following disclosures: Erika Pearce is a scientific advisory board member of ImmunoMet Therapeutics and Cour Therapeutics, and Erika Pearce and Edward Pearce are scientific advisers to Remedy Plan Therapeutics.
Journal
Nature