Novel Chemokine Responsiveness and Mobilization of Neutrophils during Sepsis

Abstract

Blood neutrophils (PMN) trafficking during inflammation is a complex process which involves endothelial and PMN adhesion molecules¹ and involvement of several types of chemotactic factors which may include lipids,² complement activation products,^3,4 and especially CXC chemokines.^5,6 Initially, PMNs interact with endothelial selectins (E, P), resulting in PMN rolling along the endothelial surface. This rolling process appears to allow PMN to become activated (“primed”) by chemokines and other mediators secreted by the endothelium, resulting in their firm adhesion to endothelial adhesion molecule (ICAM-1) via the β₂-integrins⁷ and possibly α4^8–11 and β₁-integrins in conditions of sepsis.⁸ In general, CXC chemokines, particularly macrophage inflammatory protein (MIP)-2 and KC, appear to be involved in mediating PMN influx into tissues, while CC chemokines interact predominately with macrophages and monocytes.¹² Recent findings suggest that under certain inflammatory conditions or in response to specific inflammatory stimuli, PMN may also directly interact with CC chemokines.^13–17

To date, 28 CC chemokines have been identified,¹⁸ the cellular responses to them being mediated through binding to cognate receptors. Ten different CC family chemokine receptors (CCRs) have been identified.¹⁹ Promiscuity is known to exist among CC chemokines, involving the binding of a specific chemokine to more than one receptor. For instance, MIP-1α is known to bind both CC chemokine receptors 1 (CCR1) and 5 (CCR5). However, monocyte chemoattractant protein (MCP)-1 has been shown to bind solely to the CC chemokine receptor 2 (CCR2). In addition to binding MCP-1, CCR2 also serves as a receptor for four other MCP’s (MCP-1, MCP-3, -4, and -5) and is known to be expressed on monocytes and activated T cells. CCR1 and CCR5 are known to express on human peripheral blood lymphocytes as well as monocytes.

MIP-1α has been shown to regulate lung PMN migration after systemic exposure to lipopolysaccharide (LPS), MIP-1α being thought to mediate its effect indirectly by modulating the activity of macrophages or endothelial cells such as their release of TNFα or expression of ICAM-1, respectively.²⁰ Recent in vitro studies show CCR1 can be induced on blood PMN after stimulation with specific cytokines,^15,16 suggesting the ability of PMN to respond directly to MIP-1α, which is a major ligand for CCR1. In a recent novel study, blood PMN were shown to respond to exogenous MCP-1 in a mouse model of chronic adjuvant-induced arthritis and to bind antibody to CCR2 suggesting the presence of CCR2 receptors on these PMN.¹³ MCP-1 is known to be present in the lungs of patients during several lung inflammatory disorders, including sepsis and acute respiratory distress syndrome (ARDS),^21,22 its presence correlating significantly with lung injury and mortality.²¹

Based on the above findings, we evaluated the ability of MCP-1 and MIP-1α to participate in PMN accumulation in lung after cecal ligation and puncture (CLP) or intratracheal administration of LPS. The results of the current study show that MCP-1 and MIP-1α mediate PMN accumulation in lungs of CLP mice, but not after airway instillation of LPS. In CLP mice, blood PMN were found to express mRNA for several CC chemokine receptors (CCR1, CCR2, and CCR5), to bind MCP-1 and MIP-1α, and to respond chemotactically in vitro to these chemokine receptors. In addition, serum IL-6 levels in CLP mice were found to be dependent on both MCP-1 and MIP-1α. This study suggests that neutrophil trafficking during sepsis is aberrant and that MCP-1 and MIP-1α play an important role in lung accumulation of PMN during sepsis.

Acknowledgments

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