Abstract
We have demonstrated that cardiac fibrosis arises from the differentiation of monocyte-derived fibroblasts. We present here evidence that this process requires sequential Th1 and Th2 induction promoting analogous M1 (classically activated) and M2 (alternatively activated) macrophage polarity. Our models are: (1) mice subjected to daily repetitive ischemia and reperfusion (I/R) without infarction and (2) the in vitro transmigration of human mononuclear leukocytes through human cardiac microvascular endothelium. In the mouse heart, leukocytes entered after I/R in response to monocyte chemoattractant protein-1 (MCP-1), which is the major cytokine induced by this protocol. Monocytes within the heart then differentiated into fibroblasts making collagen while bearing the markers of M2 macrophages. T cells were seen in these hearts as well as in the human heart with cardiomyopathy. In the in vitro model, transmigration of the leukocytes was likewise induced by MCP-1 and some monocytes matured into fibroblasts bearing M2 markers. In this model, the MCP-1 stimulus induced a transient Th1 and M1 response that developed into a predominantly Th2 and M2 response. An increase in the Th2 product IL-13 was present in both the human and the mouse models, consistent with its known role in fibrosis. In these simplified models, in which there is no cell death to stimulate an anti-inflammatory response, there is nonetheless a resolution of inflammation enabling a profibrotic environment. This induces the maturation of monocyte precursors into fibroblasts.
Highlights
The immune system uses similar tools whether responding to infections or sterile tissue injury
MURINE IN VIVO MODEL To quantify the number of M2 macrophages and T lymphocytes in heart tissue from shams or animals treated with the ischemia and reperfusion (I/R) protocol, we digested the heart to isolate cells and performed flow cytometry to measure the expression of the markers CD45, CD301 (M2 macrophages), and CD3 (T cells)
The source of the IL-13 may be the CD3+ T cells that transmigrated in response to monocyte chemoattractant protein-1 (MCP-1), because IL-13 was lacking in the MCP-1 knockout
Summary
The immune system uses similar tools whether responding to infections or sterile tissue injury. The liberation of heat shock proteins [2], mitochondrial DNA [3], HMGB1 (high-mobility group box 1) [4, 5], and a host of other internal components from dead cells [alarmins [6]] can trigger inflammation in the absence of infection. Others, such as adenosine [7], apoptotic cell membranes [8, 9], or self DNA [10], can at the same time initiate the anti-inflammatory response that will bring the organism back to homeostatic balance. In contrast to that schema, this report describes and defines similar responses, both proinflammatory and anti-inflammatory, in the absence of cell death and its associated signaling
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