Ccl2 and Ccl3 Mediate Neutrophil Recruitment via Induction of Protein Synthesis and Generation of Lipid Mediators

Abstract

Objective-Although the chemokines monocyte chemoattractant protein-1 (Ccl2/JE/MCP-1) and macrophage inflammatory protein-1␣ (Ccl3/MIP-1␣) have recently been implicated in neutrophil migration, the underlying mechanisms remain largely unclear. Methods and Results-Stimulation of the mouse cremaster muscle with Ccl2/JE/MCP-1 or Ccl3/MIP-1␣ induced a significant increase in numbers of firmly adherent and transmigrated leukocytes (Ͼ70% neutrophils) as observed by in vivo microscopy. This increase was significantly attenuated in mice receiving an inhibitor of RNA transcription (actinomycin D) or antagonists of platelet activating factor (PAF; BN 52021) and leukotrienes Key Words: leukocyte Ⅲ migration Ⅲ chemokines Ⅲ permeability Ⅲ basement membrane L eukocyte recruitment from the microvasculature to sites of inflammation is a key event in both innate and adaptive immunity. In this process, a diversity of adhesion molecules, proteases, and chemokines are involved regulating the sequential steps of leukocyte rolling, firm adherence, and transmigration. 1,2 Chemokines are small molecules (8 to 14 kDa) which can be classified into C, CC, CXC, and CX 3 C chemokines according to the arrangement of their N-terminal cysteine residues. Increased levels of chemokines and their respective receptors have been found in numerous pathological conditions. According to the current paradigm, chemokine receptors on circulating leukocytes are supposed to interact with chemokines presented on the venular endothelium. These interactions immediately activate leukocyte integrins which, in turn, facilitate firm adherence and transmigration of leukocytes. [3][4][5] In the past years, particularly CC chemokines have been extensively studied in various inflammatory pathologies. Concluding from these studies, CC chemokines such as monocyte chemoattractant protein-1 (Ccl2/JE/MCP-1) and macrophage inflammatory protein-1␣ (Ccl3/MIP-1␣) have been suggested to exclusively mediate the migration of monocytes and lymphocytes. [3][4][5] However, there is a growing body of evidence that Ccl2/JE/MCP-1 and Ccl3/MIP-1␣ are also critically involved in the recruitment of neutrophils. 6,7 The underlying mechanisms, however, remain largely unclear.Recently, it has been reported that both Ccl2/JE/MCP-1 and Ccl3/MIP-1␣ are able to induce the release of lipid mediators such as leukotriene-B 4 (LTB 4 ). 8 -10 The functional relevance of endogenously generated lipid mediators including prostaglandins, leukotrienes, and PAF for each single step of the recruitment process of neutrophils elicited by Ccl2/JE/ In addition to leukocyte migration, Ccl2/JE/MCP-1 and Ccl3/MIP-1␣ have been implicated in the control of microvascular permeability. 11,12 Moreover, Ccl3/MIP-1␣ has recently been demonstrated to induce remodeling of the perivascular basement membrane, a process which might promote microvascular leakage during inflammatory conditions. 11 The contribution of neutrophils to these events, however, has not yet been studied.Therefore, the objective of the present study...

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