Cytokine amplification and macrophage effector functions in aortic inflammation and abdominal aortic aneurysm formation

Talha Ijaz, Ronald Tilton, Allan R. Brasier

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

On April 29, 2015, Son and colleagues published an article entitled "Granulocyte macrophage colony-stimulating factor (GM-CSF) is required for aortic dissection/intramural haematoma" in Nature Communications. The authors observed that the heterozygous Kruppel-like transcription factor 6 (KLF6) deficiency or absence of myeloid-specific KLF6 led to upregulation of macrophage GM-CSF expression, promoted the development of aortic hematoma/dissection, and stimulated abdominal aortic aneurysm (AAA) formation when the vessel wall was subjected to an inflammatory stimulus. The additional findings of increased adventitial fibrotic deposition, marked infiltration of macrophages, and increased expression of matrix metalloprotease-9 (MMP-9) and IL-6 were blocked with neutralizing GM-CSF antibodies, or recapitulated in normal mice with excess GM-CSF administration. The authors concluded that GM-CSF is a key regulatory molecule in the development of AAA and further suggested that activation of GM-CSF is independent of the transforming growth factor β (TGFβ)-Smad pathway associated with the Marfan aortic pathology. In this perspective, we expand on this mechanism, drawing from previous studies implicating a similar essential role for IL-6 signaling in macrophage activation, Th17 expansion and aortic dissections. We propose a sequential "two-hit" model of vascular inflammation involving initial vascular injury followed by recruitment of Ly6Chi macrophages. Aided by fibroblast interactions inflammatory macrophages produce amplification of IL-6 and GM-CSF expression that converge on a common, pathogenic Janus kinase (JAK)- signal transducers and activations of transcription 3 (STAT3) signaling pathway. This pathway stimulates effector functions of macrophages, promotes differentiation of Th17 lymphocytes and enhances matrix metalloproteinase expression, ultimately resulting in deterioration of vascular wall structural integrity. Further research evaluating the impact of interventions modulating this common JAK-STAT3 pathway may yield new therapeutic interventions for late stages of vascular expansion in inflammation driven aortic disease.

Original languageEnglish (US)
Pages (from-to)E746-E754
JournalJournal of Thoracic Disease
Volume8
Issue number8
DOIs
StatePublished - 2016

Fingerprint

Abdominal Aortic Aneurysm
Granulocyte-Macrophage Colony-Stimulating Factor
Macrophages
Cytokines
Inflammation
Kruppel-Like Transcription Factors
Janus Kinases
Blood Vessels
Dissection
Interleukin-6
Transducers
Hematoma
Transcriptional Activation
Adventitia
Aortic Diseases
Macrophage Activation
Vascular System Injuries
Transforming Growth Factors
Metalloproteases
Matrix Metalloproteinases

Keywords

  • Angiotensin II
  • Granulocyte macrophage colony-stimulating factor (GM-CSF)
  • IL-6
  • Janus kinase (JAK)
  • Kruppel-like transcription factor 6 (KLF6)
  • Signal transducers and activations of transcription (STAT)

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Cytokine amplification and macrophage effector functions in aortic inflammation and abdominal aortic aneurysm formation. / Ijaz, Talha; Tilton, Ronald; Brasier, Allan R.

In: Journal of Thoracic Disease, Vol. 8, No. 8, 2016, p. E746-E754.

Research output: Contribution to journalArticle

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abstract = "On April 29, 2015, Son and colleagues published an article entitled {"}Granulocyte macrophage colony-stimulating factor (GM-CSF) is required for aortic dissection/intramural haematoma{"} in Nature Communications. The authors observed that the heterozygous Kruppel-like transcription factor 6 (KLF6) deficiency or absence of myeloid-specific KLF6 led to upregulation of macrophage GM-CSF expression, promoted the development of aortic hematoma/dissection, and stimulated abdominal aortic aneurysm (AAA) formation when the vessel wall was subjected to an inflammatory stimulus. The additional findings of increased adventitial fibrotic deposition, marked infiltration of macrophages, and increased expression of matrix metalloprotease-9 (MMP-9) and IL-6 were blocked with neutralizing GM-CSF antibodies, or recapitulated in normal mice with excess GM-CSF administration. The authors concluded that GM-CSF is a key regulatory molecule in the development of AAA and further suggested that activation of GM-CSF is independent of the transforming growth factor β (TGFβ)-Smad pathway associated with the Marfan aortic pathology. In this perspective, we expand on this mechanism, drawing from previous studies implicating a similar essential role for IL-6 signaling in macrophage activation, Th17 expansion and aortic dissections. We propose a sequential {"}two-hit{"} model of vascular inflammation involving initial vascular injury followed by recruitment of Ly6Chi macrophages. Aided by fibroblast interactions inflammatory macrophages produce amplification of IL-6 and GM-CSF expression that converge on a common, pathogenic Janus kinase (JAK)- signal transducers and activations of transcription 3 (STAT3) signaling pathway. This pathway stimulates effector functions of macrophages, promotes differentiation of Th17 lymphocytes and enhances matrix metalloproteinase expression, ultimately resulting in deterioration of vascular wall structural integrity. Further research evaluating the impact of interventions modulating this common JAK-STAT3 pathway may yield new therapeutic interventions for late stages of vascular expansion in inflammation driven aortic disease.",
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AB - On April 29, 2015, Son and colleagues published an article entitled "Granulocyte macrophage colony-stimulating factor (GM-CSF) is required for aortic dissection/intramural haematoma" in Nature Communications. The authors observed that the heterozygous Kruppel-like transcription factor 6 (KLF6) deficiency or absence of myeloid-specific KLF6 led to upregulation of macrophage GM-CSF expression, promoted the development of aortic hematoma/dissection, and stimulated abdominal aortic aneurysm (AAA) formation when the vessel wall was subjected to an inflammatory stimulus. The additional findings of increased adventitial fibrotic deposition, marked infiltration of macrophages, and increased expression of matrix metalloprotease-9 (MMP-9) and IL-6 were blocked with neutralizing GM-CSF antibodies, or recapitulated in normal mice with excess GM-CSF administration. The authors concluded that GM-CSF is a key regulatory molecule in the development of AAA and further suggested that activation of GM-CSF is independent of the transforming growth factor β (TGFβ)-Smad pathway associated with the Marfan aortic pathology. In this perspective, we expand on this mechanism, drawing from previous studies implicating a similar essential role for IL-6 signaling in macrophage activation, Th17 expansion and aortic dissections. We propose a sequential "two-hit" model of vascular inflammation involving initial vascular injury followed by recruitment of Ly6Chi macrophages. Aided by fibroblast interactions inflammatory macrophages produce amplification of IL-6 and GM-CSF expression that converge on a common, pathogenic Janus kinase (JAK)- signal transducers and activations of transcription 3 (STAT3) signaling pathway. This pathway stimulates effector functions of macrophages, promotes differentiation of Th17 lymphocytes and enhances matrix metalloproteinase expression, ultimately resulting in deterioration of vascular wall structural integrity. Further research evaluating the impact of interventions modulating this common JAK-STAT3 pathway may yield new therapeutic interventions for late stages of vascular expansion in inflammation driven aortic disease.

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