IL-1 induces proinflammatory leukocyte infiltration and regulates fibroblast phenotype in the infarcted myocardium

Amit Saxena, Wei Chen, Ya Su, Vikrant Rai, Olisambu U. Uche, Na Li, Nikolaos G. Frangogiannis

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

In the infarcted myocardium, activation of the inflammatory cascade clears the wound from dead cells, whereas stimulating matrix degradation and chamber dilation, thus contributing to the development of heart failure. IL-1 is critically involved in the postinfarction inflammatory reaction and mediates adverse dilative remodeling. We hypothesized that IL-1 may regulate postinfarction repair and remodeling through cell-specific actions on leukocytes and fibroblasts. Flow cytometry demonstrated that in mouse infarcts, early recruitment of proinflammatory Ly6Chi cells expressing IL-1R1, the signaling receptor for IL-1, was followed by infiltration with cells expressing the decoy receptor, IL-1R2. Increased expression of IL-1R2 may serve to terminate IL-1-driven inflammation after infarction. Loss of IL-1 signaling in IL-1R1 null mice globally attenuated leukocyte recruitment, reducing the number of infiltrating Ly6Chi and Ly6Clo cells. Nonmyeloid CD11b2 cells harvested during the inflammatory phase of cardiac repair exhibited marked upregulation of chemokines and cytokines; their inflammatory activation was IL-1R1 dependent. Moreover, IL-1β attenuated TGF-b-induced contractile activity of fibroblasts populating collagen pads, attenuated a-smooth muscle actin expression, and stimulated matrix metalloproteinase synthesis in an IL-1R1-dependent manner. The effects of IL-1 on TGF-b responses in cardiac fibroblasts were not due to direct effects on Smad activation, but were associated with endoglin suppression and accentuated expression of bone morphogenetic protein and activin membrane-bound inhibitor, a negative regulator of TGF-b signaling. IL-1 may orchestrate fibroblast responses in the infarct; early stimulation of fibroblast IL-1R1 signaling during the inflammatory phase may prevent premature activation of a matrix-synthetic contractile phenotype until the wound is cleared, and the infarct microenvironment can support mesenchymal cell growth.

Original languageEnglish (US)
Pages (from-to)4838-4848
Number of pages11
JournalJournal of Immunology
Volume191
Issue number9
DOIs
StatePublished - Nov 1 2013

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Interleukin-1
Myocardium
Leukocytes
Fibroblasts
Phenotype
Activins
Bone Morphogenetic Proteins
Interleukin-1 Receptors
Wounds and Injuries
Matrix Metalloproteinases
Chemokines
Infarction
Smooth Muscle
Actins
Dilatation
Flow Cytometry
Up-Regulation
Collagen
Heart Failure
Cytokines

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

IL-1 induces proinflammatory leukocyte infiltration and regulates fibroblast phenotype in the infarcted myocardium. / Saxena, Amit; Chen, Wei; Su, Ya; Rai, Vikrant; Uche, Olisambu U.; Li, Na; Frangogiannis, Nikolaos G.

In: Journal of Immunology, Vol. 191, No. 9, 01.11.2013, p. 4838-4848.

Research output: Contribution to journalArticle

Saxena, Amit ; Chen, Wei ; Su, Ya ; Rai, Vikrant ; Uche, Olisambu U. ; Li, Na ; Frangogiannis, Nikolaos G. / IL-1 induces proinflammatory leukocyte infiltration and regulates fibroblast phenotype in the infarcted myocardium. In: Journal of Immunology. 2013 ; Vol. 191, No. 9. pp. 4838-4848.
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AB - In the infarcted myocardium, activation of the inflammatory cascade clears the wound from dead cells, whereas stimulating matrix degradation and chamber dilation, thus contributing to the development of heart failure. IL-1 is critically involved in the postinfarction inflammatory reaction and mediates adverse dilative remodeling. We hypothesized that IL-1 may regulate postinfarction repair and remodeling through cell-specific actions on leukocytes and fibroblasts. Flow cytometry demonstrated that in mouse infarcts, early recruitment of proinflammatory Ly6Chi cells expressing IL-1R1, the signaling receptor for IL-1, was followed by infiltration with cells expressing the decoy receptor, IL-1R2. Increased expression of IL-1R2 may serve to terminate IL-1-driven inflammation after infarction. Loss of IL-1 signaling in IL-1R1 null mice globally attenuated leukocyte recruitment, reducing the number of infiltrating Ly6Chi and Ly6Clo cells. Nonmyeloid CD11b2 cells harvested during the inflammatory phase of cardiac repair exhibited marked upregulation of chemokines and cytokines; their inflammatory activation was IL-1R1 dependent. Moreover, IL-1β attenuated TGF-b-induced contractile activity of fibroblasts populating collagen pads, attenuated a-smooth muscle actin expression, and stimulated matrix metalloproteinase synthesis in an IL-1R1-dependent manner. The effects of IL-1 on TGF-b responses in cardiac fibroblasts were not due to direct effects on Smad activation, but were associated with endoglin suppression and accentuated expression of bone morphogenetic protein and activin membrane-bound inhibitor, a negative regulator of TGF-b signaling. IL-1 may orchestrate fibroblast responses in the infarct; early stimulation of fibroblast IL-1R1 signaling during the inflammatory phase may prevent premature activation of a matrix-synthetic contractile phenotype until the wound is cleared, and the infarct microenvironment can support mesenchymal cell growth.

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