Role Unearthed for CRELD1 in Immune Homeostasis During Aging

Scientists from the University of Bonn in Germany have discovered that a protein known as CRELD1, classically regarded as important to human development during pregnancy, is also of relevance to the regulation of the immune system during adulthood.

By analyzing differences in CRELD1 expression among humans, the researchers found that expression levels of the protein are associated with “strong phenotypic, functional, and transcriptional differences” that have important implications for the homeostasis of the immune system during aging.

“We had previously studied the function of Creld1 and shown that it is crucial for embryonic heart development (Mass and Wachten, et al., Dev Cell, 2014),” senior author Dr. Anna Aschenbrenner told ImmunoFrontiers. “As expression data in the publicly available databases indicated CRELD1 to be ubiquitously expressed throughout the body, we were wondering about its function in adult life.”

“We employed a combination of analyses of large human cohort studies, in vivo and in vitro experiments based on a genetic mouse model as well as cell line-based molecular biology work, RNA-sequencing and bioinformatic analysis approaches.”

“We discovered that CRELD1 is an important modulator of immune homeostasis in mice and humans. Low CRELD1 expression is associated with low naïve CD4+ T cell numbers in peripheral blood, which is also a phenotype of the aged immune system. Furthermore, low CRELD1 expression is associated with a cellular immunosenescence signature.”

“We generated a specific mouse model and showed that genetic loss of Creld1 is indeed the cause for the loss of T cells. Transcriptome analysis of T cells lacking Creld1 in combination with a series of in vivo and in vitro experiments linked Creld1 function to homeostasis, apoptosis and cell activation. We further demonstrated that the Creld1 acts at the plasma membrane where it affects canonical and non-canonical Wnt signalling.”

“To understand the scope and the significance of our findings for human biology, we validated our findings in three additional independent large human studies (CEDAR; ImmVar; own new data compilation), including altogether more than 4,500 individuals.”

“In these independent studies, individuals with low levels of CRELD1 showed an enrichment of the same signatures observed in the murine Creld1-deficient T cells (loss of Wnt signalling and gain of apoptotic signatures).”

“Moreover, this was not restricted to CD4+ T cells but also observed in CD8+ T cells, B cells and monocytes, indicating a general cellular mechanism regulating cell survival and as a consequence immunosenescence.”

The team’s research is the first to implicate a role for CRELD1 in the regulation of the immune system and could enhance our understanding of how the balance of immune cell populations is calibrated during aging.

The study, published in the scientific journal Nature Immunology under the title “CRELD1 modulates homeostasis of the immune system in mice and humans”, included co-authors from Radboud University Medical Center in the Netherlands, University of Liège in Belgium, and Hannover Medical School in Germany in addition to the University of Bonn. Dr. Anna Aschenbrenner was the senior author.

“CRELD1 function in adult life was previously elusive. This is the first report of its implication in immune homeostasis,” Dr. Aschenbrenner continued. “The changes seen with low CRELD1 expression are reminiscent of those usually observed in people with an ‘aged’ immune system, which have been connected to many age-related diseases as well as susceptibility to infections.”

“Understanding the underpinnings of homeostasis of the immune system is important to understand the etiology of diseases – and we have added another important modulator to consider in this context.”

The scientists plan to apply methods developed from their research to enhancing the understanding of molecular and cellular processes driven by other genes, including those, like CRELD1, whose function may not be well characterized.

“We want to extend the analysis approach that we developed in this study to utilise human system level information to directly study molecular and cellular functions of individual genes and make it accessible to the scientific community, especially also to those scientists with less bioinformatic training,” stated Dr. Aschenbrenner.

“There is already so much human experimental data publicly available, and with omics approaches finding their way into the clinics this field will continue to grow. Harnessing this accumulated knowledge will benefit basic researchers to build new hypotheses, design more targeted experiments and link their research in genetic models back to humans.”

Dr. Aschenbrenner’s take-home message for readers: “The importance of knowledge on the factors regulating pre-mature aging of our immune system has become especially clear this year, seeing how some people cope well with a SARS-CoV-2 infection while others suffer from severe COVID-19.”

“There is still much to learn about our immune system and all the different components regulating its proper functioning, which we need to continue to explore to be able to understand the determinants of individual disease courses as well as necessary drivers of staying healthy.”

Learn more about the research from the University of Bonn’s press release.

Read more about the latest research in the field of immunology from ImmunoFrontiers.