This key enzyme governs immune cell maturation and survival, influencing our understanding of aging and disease
An enzyme that controls the maturation and long-term survival of immune cells called macrophages has been discovered, with implications for research on aging and inflammatory disease.
Research led by scientists at the Johns Hopkins Kimmel Cancer Center, Bloomberg~Kimmel Institute for Cancer Immunotherapy and the Johns Hopkins Bloomberg School of Public Health (all MD, USA) has identified an enzyme required for the differentiation and maintenance of tissue-resident macrophages, which are essential for organ health.
Virtually all tissues are populated by tissue-resident macrophages – self-renewing, long-lived immune cells that maintain tissue health and homeostasis by clearing damaged cells and debris. They usually form during embryogenesis; however, during tissue damage, bone-marrow-derived monocytes enter tissues and differentiate into tissue-resident macrophages, replenishing the macrophage population.
When things go awry with the monocyte-to-tissue-resident macrophage transition, it can contribute to inflammation and disease, and yet, despite its significance, we know very little about the mechanisms that control it across tissues.
Previous research has exposed the role of deoxyhypusine synthase (DHPS), which catalyzes the modification of lysine to deoxyhypusine in the translation factor eIF5A, deficiency in myeloid cell inflammation. In obese mice, for example, it suppresses inflammatory macrophage accumulation in adipose tissue and improves glucose tolerance.
To further explore the importance of this enzyme in immune cells, the team generated mice with DHPS deleted in myeloid cells, including monocytes and macrophages, and used flow cytometry and imaging to identify macrophages within their tissues. In rodents with DHPS knocked down, tissue-resident macrophages exhibited defects in the peritoneum, lung, liver, heart, brain, spleen and kidney, resulting in persistent but ultimately futile monocyte influx.
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Then, transcriptional analyses of DHPS-deficient macrophages indicated a block in their ability to differentiate into mature tissue-resident macrophages, while proteomics revealed defects in cell adhesion and signaling pathways. Similarly, sequencing of ribosome-engaged transcripts highlighted a subset of mRNAs involved in cell adhesion and signaling that rely on DHPS for efficient translation.
Imaging studies showed that macrophages lacking DHPS had abnormal morphology and tissue interactions, and functional assays demonstrated that they were defective in critical tissue-resident macrophage functions, including clearing dead cells and tissue maintenance.
Taken together, these findings pinpoint DHPS as a regulator of the pathway that drives the differentiation of monocyte-derived macrophages into tissue-resident macrophages. As a result, it could represent a promising therapeutic target for a number of conditions.
“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,” commented co-senior author Daniel Puleston.
Next, the team intends to focus on identifying the full suite of DHPS-dependent proteins and determining how this pathway is implicated in specific diseases.
“This is a very fundamental pathway for these cells,” study author Erika Pearce added. “Understanding when and where macrophages depend on this process, and when it might be beneficial to enhance or inhibit, is an important next step.”