modulation of macrophage inflammatory responses by angiotensin converting enzyme Público
Okwan-Duodu, Derick (2013)
Published
Abstract
The renin angiotensin system (RAS), critical for blood pressure control, is emerging as an important modulator of the immune response. Angiotensin-converting enzyme (ACE) is a key member of the RAS, in that it participates in the generation of the effector octapeptide angiotensin II from angiotensinogen. To understand the role of ACE in the immune response, we substituted control of the ACE gene from its endogenous promoter to c-fms promoter, with a resulting over-expression of ACE in myelomonocytic lineage cells such as neutrophils, monocytes and macrophages. These mice, referred to as ACE 10/10, are resistant to tumor growth and bacterial infections (Listeria monocytogenes and methicilin-resistant S. aureus). The upregulation of iNOS and other pro-inflammatory cytokines (TNF-α, IL-12) were critical to the immune changes in these mice. In vitro, ACE 10 macrophages potently destroyed tumor cells and bacteria, exhibiting strong hallmarks of the classically -activated M1 macrophage phenotype. We found that the biochemical changes were associated with increased expression of C/EBPα, a transcription factor crucial for development, maturation and differentiation of myeloid cells. Because C/EBPα has been shown to drive myelomonocytic cell maturation, it is likely that the increased resistance to tumors was in part due to a diminution of immature myelomonocytic cells that participate in tumor-induced myeloid-mediated immunosuppression. In both resistance to tumors and bacterial infection, the phenotype of ACE 10/10 mice was transferable by bone marrow transplantation to recipient WT animals, suggesting immune-mediated effects, rather than mere alteration of ACE in other tissues. Pharmacological ACE inhibition reversed the phenotypes observed and suggested that the catalytic activity of ACE was an important mediator of the inflammatory responses. However, pharmacological and genetic blockade of angiotensin II (Ang II) and its receptor AT-1 (AT1R) had minimal effects in the ACE 10/10, suggesting an ACE-mediated phenomenon independent of Ang II, the most well described bioactive product of ACE activity. Altogether, these data reveal remarkable ability of the blood pressure regulating peptidase ACE to potently modify the behavior of myelomonocytic lineage cells for anti-tumor and bacterial immunity.
Table of Contents
Table of Contents
CHAPTER1:INTRODUCTION……………………………………………………… 1
The History of the Renin-Angiotensin System…………………………….. 1
ACE- Biochemistry and Physiology………………………………………….. 3
Angiotensin II - physiology ….…………………………………………… 5
Angiotensin II Receptors …………………………………………………... 6
Local RAS……………………………………………………………………… 7
Transgenic Models to Investigate Tissue RAS …………………………….. 8
ACE 1 ……………………………………………………………………….. 12
ACE 2 ………………………………………………………………………… 12
ACE 3 ………………………………………………………………………… 16
ACE 10 .…………………………………………………………………………18
RAS in Immunity………………………………………………………………...20
The RAS in Monocyte/Macrophages Function ……………………………… . 24
References……………………………………………………………………… 29
CHAPTER 2: RESPONSE OF ACE10/10 MICE TO INFECTION ………………… 44
Title Page ……………………………………………………………………46
Abstract …………………………………………………………………….. 47
Introduction……………………………………………………………....…. 48
Methods …………………………………………………………………….. 51
Results ……………………………………………………………………….... 56
Discussion ……………………………………………………………………... 81
Acknowledgement ……………………………………………………………...84
References ………………………………………………………………………85
CHAPTER 3: EFFECT OF ACE ON MYELOMONOCYTIC CELLS ……………….92
Title Page ….………………………………………………………………… 94
Abstract.……………………………………………………………………… 95
Introduction ………………………………………………………………….. 96
Methods …………………………………………………………………… ... 99
Results………………………………………………………………………. 103
Discussion ………………………………………………………………….. 103
Acknowledgement …………………………………………………………. 125
References ……………………………………………………………….......126
CHAPTER 4: CONCLUSIONS AND FUTURE DIRECTIONS ……………………..132
ACE over-expression and myelomonocytic cell function…………………..132
C/EBPα: the potential link between RAS and Adiposity …………………. 136
Challenges of the ACE 10 …………………………………………………. 137
ACE 10 and Atherosclerosis ………………………………………………. 139
ACE 10 and Granulomas …………………………………………………...141
ACE 10, the Kidney and Hypertension ………………………………..........142
ACE 10 and Brain …………………………………………………………143
References ……………………………………………………………….....145
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