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Targeting Interleukin-1β Reduces Leukocyte Production After Acute Myocardial Infarction
Hendrik B Sager1, Timo Heidt1, Maarten Hulsmans1
1From Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, Boston, MA (H.B.S., T.H., M.H., P.D., G.C., M.S., G.R.W., B.T., Y.I., Y.S., R.W., F.K.S., M.N.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).
Background:
Myocardial infarction (MI) is an ischemic wound that recruits millions of leukocytes. MI-associated blood leukocytosis correlates inversely with patient survival, yet the signals driving heightened leukocyte production after MI remain incompletely understood.
Methods And Results:
With the use of parabiosis surgery, this study shows that soluble danger signals, among them interleukin-1β, increase bone marrow hematopoietic stem cell proliferation after MI. Data obtained in bone marrow reconstitution experiments reveal that interleukin-1β enhances hematopoietic stem cell proliferation by both direct actions on hematopoietic cells and through modulation of the bone marrow's hematopoietic microenvironment. An antibody that neutralizes interleukin-1β suppresses these effects. Anti-interleukin-1β treatment dampens the post-MI increase in hematopoietic stem cell proliferation. Consequently, decreased leukocyte numbers in the blood and infarct reduce inflammation and diminish post-MI heart failure in ApoE(-/-) mice with atherosclerosis.
Conclusions:
The presented insight into post-MI bone marrow activation identifies a mechanistic target for muting inflammation in the ischemically damaged heart.
Insights
Interleukin-1β signals increase hematopoietic stem cell proliferation after myocardial infarction (MI), leading to more leukocytes. Blocking this signal reduces inflammation and heart failure post-MI.
Area of Science:
- Immunology
- Hematology
- Cardiovascular Science
Background:
- Myocardial infarction (MI) is an ischemic injury that triggers significant leukocyte recruitment.
- Elevated blood leukocyte counts post-MI are linked to poorer patient survival.
- The specific signals driving increased leukocyte production after MI are not fully understood.
Purpose of the Study:
- To investigate the mechanisms by which myocardial infarction (MI) stimulates bone marrow hematopoietic stem cell proliferation.
- To identify key molecular signals involved in post-MI leukocytosis.
- To evaluate the therapeutic potential of targeting these signals to mitigate adverse cardiac remodeling and heart failure.
Main Methods:
- Parabiosis surgery to assess systemic signaling.
- Bone marrow reconstitution experiments to evaluate hematopoietic stem cell behavior.
- In vivo administration of anti-interleukin-1β antibodies.
- Assessment of leukocyte counts, inflammation, and cardiac function in ApoE(-/-) mice with atherosclerosis.
Main Results:
- Soluble danger signals, including interleukin-1β (IL-1β), were identified as drivers of hematopoietic stem cell proliferation post-MI.
- IL-1β directly acts on hematopoietic cells and modulates the bone marrow microenvironment to enhance proliferation.
- Neutralization of IL-1β with antibodies suppressed post-MI hematopoietic stem cell proliferation.
- Anti-IL-1β treatment reduced leukocyte counts in blood and infarct tissue, thereby decreasing inflammation and diminishing post-MI heart failure in a mouse model.
Conclusions:
- Post-MI bone marrow activation is mediated by signals like IL-1β.
- Targeting IL-1β represents a potential therapeutic strategy to reduce inflammation in the damaged heart.
- Modulating bone marrow response to MI can impact cardiac outcomes and heart failure progression.
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