Abstract
BackgroundMIF is a critical mediator of the host defense, and is involved in both acute and chronic responses in the lung. Neutralization of MIF reduces neutrophil accumulation into the lung in animal models. We hypothesized that MIF, in the alveolar space, promotes neutrophil accumulation via activation of the CD74 receptor on macrophages.MethodsTo determine whether macrophage CD74 surface expression contributes MIF-induced neutrophil accumulation, we instilled recombinant MIF (r-MIF) into the trachea of mice in the presence or absence of anti-CD74 antibody or the MIF specific inhibitor, ISO-1. Using macrophage culture, we examined the downstream pathways of MIF-induced activation that lead to neutrophil accumulation.ResultsIntratracheal instillation of r-MIF increased the number of neutrophils as well as the concentration of macrophage inflammatory protein 2 (MIP-2) and keratinocyte-derived chemokine (KC) in BAL fluids. CD74 was found to be expressed on the surface of alveolar macrophages, and MIF-induced MIP-2 accumulation was dependent on p44/p42 MAPK in macrophages. Anti-CD74 antibody inhibited MIF-induced p44/p42 MAPK phosphorylation and MIP-2 release by macrophages. Furthermore, we show that anti-CD74 antibody inhibits MIF-induced alveolar accumulation of MIP-2 (control IgG vs. CD74 Ab; 477.1 ± 136.7 vs. 242.2 ± 102.2 pg/ml, p < 0.05), KC (1796.2 ± 436.1 vs. 1138.2 ± 310.2 pg/ml, p < 0.05) and neutrophils (total number of neutrophils, 3.33 ± 0.93 × 104 vs. 1.90 ± 0.61 × 104, p < 0.05) in our mouse model.ConclusionMIF-induced neutrophil accumulation in the alveolar space results from interaction with CD74 expressed on the surface of alveolar macrophage cells. This interaction induces p44/p42 MAPK activation and chemokine release. The data suggest that MIF and its receptor, CD74, may be useful targets to reduce neutrophilic lung inflammation, and acute lung injury.
Highlights
migration inhibitory factor (MIF) is a critical mediator of the host defense, and is involved in both acute and chronic responses in the lung
MIF induces neutrophil accumulation into the lung We have previously reported that MIF has the ability to induce neutrophil accumulation into the alveolar space of mice [25]
This study shows that CD74 is expressed on the cell surface of alveolar macrophages, and potentially contributes to MIF-induced neutrophil accumulation into the alveolar space
Summary
MIF is a critical mediator of the host defense, and is involved in both acute and chronic responses in the lung. Neutralization of MIF reduces neutrophil accumulation into the lung in animal models. Macrophage migration inhibitory factor (MIF) is an inflammatory mediator of innate and adaptive immune responses. Plasma MIF concentrations are elevated in patients with inflammatory diseases such as sepsis [2], ARDS [3,4] or rheumatoid arthritis [5]. In lung inflammation and injury models, MIP-2 and KC play key roles in neutrophil accumulation into the lungs [10]. Neutrophils are an important component of the inflammatory response in acute lung injury [11,12]. The elimination of neutrophils can markedly decrease the severity of lung injury in animal lung inflammation models [13]. MIF levels are increased in BAL fluid in lipopolysaccharide (LPS)-induced lung injury model [14], and MIF neutralizing antibody blocks LPS-induced pulmonary neutrophil accumulation in animal models [15,16], suggesting that MIF can influence neutrophil accumulation into the lungs
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