Cytokine Triggers Immune Response at Expense of Blood Renewal

Heightened levels of the cytokine protein IL-1 in the blood are known as a common denominator in a broad range of diseases involving chronic inflammation, including obesity, diabetes, atherosclerosis, rheumatoid arthritis and lupus. Excessive IL-1 is known to correlate with increased production by the bone marrow of aggressive immune cells, which can damage other tissues, at the expense of cells that maintain healthy blood and immune system. But whether IL-1 itself was causing these changes, or merely acting as a bystander was not clearly understood.

Now stem cell biologists at UC San Francisco have demonstrated that IL-1 itself directly transforms the blood system by driving blood stem cells (termed “hematopoietic stem cells” or HSCs) in the bone marrow to switch away from their restorative, rejuvenating role in blood renewal and toward emergency production of immune cells.

“IL-1 is a double-edged sword,” said study senior author Emmanuelle Passegué, PhD, a professor of medicine at the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. “It’s a magnificent system for responding to acute injury or infection: When you need an immune response, you need it now, and IL-1 is critical for communicating this information and stimulating the production of immune cells by the bone marrow. But leaving on this signal is not good for the health of the organism. It damages the blood system and leads to an overproduction of immune cells that contribute to chronic inflammatory disease.”

Fortunately, the researchers also demonstrate that the negative consequences of chronic IL-1 exposure on blood stem cells are rapidly reversed when the immune molecule is removed, supporting ongoing clinical attempts to use IL-1-blocking drugs to treat diseases of chronic inflammation such as cardiovascular disease, diabetes, and arthritis and even as a way to slow aging.

IL-1 Can Switch Blood Stem Cells to 'Red Alert'

In their new paper — published online April 25, 2016, in the journal Nature Cell Biology — Passegué and her team performed experiments in cell culture as well as in live mice showing that IL-1 exposure directly drives HSCs toward emergency production of myeloid cells of the acute immune system – such as monocytes, neutrophils and macrophages — by activating a molecular network driven by the myeloid commitment gene Pu.1.

Additional mouse experiments showed that while brief IL-1 exposure produces a wave of myeloid cells capable of responding to tissue damage or fighting off an acute infection without significant negative consequences, chronic exposure to IL-1 for up to 70 days drastically impaired the ability of HSCs in the bone marrow to perform their normal, non-emergency role of maintaining and regenerating the blood and immune systems.

“IL-1 reshapes the blood system at its most primitive level,” Passegué said. “It biases the bone marrow to respond to emergencies, but at the expense of blood renewal, which directly impacts the functionality of the blood system in chronic inflammatory conditions.”

Fortunately, the researchers discovered that the negative effects of IL-1 on HSCs are short lived. When the researchers took blood stem cells from mice that had been chronically exposed to IL-1, deprived them of IL-1 for a few weeks, then transplanted them into mice whose blood marrow had been fatally damaged, the transplanted cells flourished, regenerating a normal blood system with virtually no sign of their long previous exposure to IL-1. These results support the notion that blocking IL-1’s effects on the stem cells of the bone marrow may be a potent treatment for chronic inflammation.

“IL-1 had been implicated in the development and progression of type 2 diabetes before, but its exact role had not been established,” said Matthias Hebrok, PhD, director of the Diabetes Center at UCSF. “This elegant study pointing to IL-1 as a critical regulator of cellular inflammation should open up new avenues of research into the early triggers of diabetes.”

Blocking IL-1 May Reverse Effects of Chronic Inflammation

The results uncover a new regulatory circuit that clarifies how IL-1 shifts the blood-generating cells of the bone marrow from self-renewal toward acute needs, with important consequences for the functionality of the blood system in chronic inflammatory conditions. In addition, the results suggest that bone marrow transplant failures may in some cases be due to high levels of IL-1, which is produced in response to bone marrow injury and could cause HSCs to fail the massive regeneration challenge required for successful transplantation.

Importantly, Passegué says, the discovery that the damaging effects of IL-1 on HSC function are reversible has important translational implications for the use of existing FDA-approved IL-1 blockade therapies to restore HSC function and blood homeostasis for millions of patients suffering from chronic inflammation worldwide. “Understanding this mechanism helps us understand why these drugs are such promising treatments for patients with chronic inflammation,” she said.

Passegué suspects that IL-1 could play a similarly double-edged role in a variety of tissues via direct reprogramming of their stem cell populations. If so, she says, reducing chronic IL-1 exposure, may be an important approach for improving stem cell health and tissue function in the context of both inflammatory disease and normal aging.

Researchers on the paper include first author and co-corresponding author Eric M. Pietras, PhD; Cristina Mirantes-Barbeito; Sarah Fong; SiYi Zhang; Ranjani Lakshminarasimhan; Chih Peng Ching; and José-Marc Techner of UCSF; Dirk Loeffler, PhD, and Tim Schroeder, PhD, of ETH Zurich, Switzerland; Larisa V. Kovtonyuk, PhD, and Markus G. Manz, MD, of University Hospital and University of Zurich, Switzerland; Britta Will, PhD, and Ulrich Steidl, MD, PhD of Albert Einstein Medical College, New York; and Claus Nerlov, PhD, of Oxford University. Pietras is now an assistant professor at the University of Colorado Denver.

The researchers were supported by the National Institutes of Health (grants R01 HL092471, F32 HL106989 and K01 DK09831), the California Institute of Regenerative Medicine (CIRM), the Institute of Health Carlos III, the Swiss National Science Foundation, and the Leukemia and Lymphoma Society. The researchers declare no competing financial interests.

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital San Francisco, and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.