The long pentraxin (PTX) 3 is produced by macrophages and myeloid dendritic cells in response to Toll-like receptor agonists and represents a nonredundant component of humoral innate immunity against selected pathogens. We report that, unexpectedly, PTX3 is stored in specific granules and undergoes release in response to microbial recognition and inflammatory signals. Released PTX3 can partially localize in neutrophil extracellular traps formed by extruded DNA. Eosinophils and basophils do not contain preformed PTX3. PTX3-deficient neutrophils have defective microbial recognition and phagocytosis, and PTX3 is nonredundant for neutrophil-mediated resistance against Aspergillus fumigatus. Thus, neutrophils serve as a reservoir, ready for rapid release, of the long PTX3, a key component of humoral innate immunity with opsonic activity.

Pentraxins are a superfamily of conserved proteins involved in the acute-phase response and innate immunity. Pentraxin 3 (PTX3), a prototypical member of the long pentraxin subfamily, is a key component of the humoral arm of innate immunity that is essential for resistance to certain pathogens. A regulatory role for pentraxins in inflammation has long been recognized, but the underlying mechanisms remain unclear. Here we report that PTX3 bound P-selectin and attenuated neutrophil recruitment at sites of inflammation. PTX3 released from activated leukocytes functioned locally to dampen neutrophil recruitment and regulate inflammation. Antibodies have glycosylation-dependent regulatory effect on inflammation. Therefore, PTX3, which is an essential component of humoral innate immunity, and immunoglobulins share functional outputs, including complement activation, opsonization and, as shown here, glycosylation-dependent regulation of inflammation.

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Background-Immune responses participate in several phases of atherosclerosis; there is, in fact, increasing evidence that both adaptive immunity and innate immunity tightly regulate atherogenesis. Pentraxins are a superfamily of acute-phase proteins that includes short pentraxins such as C-reactive protein or long pentraxins such as PTX3, a molecule acting as the humoral arm of innate immunity. To address the potential role of PTX3 in atherogenesis, we first investigated the expression of PTX3 during atherogenesis, generated double-knockout mice lacking PTX3 and apolipoprotein E, and then studied the effect of murine PTX3 deficiency on plasma lipids, atherosclerosis development, and gene expression pattern in the vascular wall. Methods and Results-PTX3 expression increases in the vascular wall of apolipoprotein E-knockout mice from 3 up to 18 months of age. Double-knockout mice lacking PTX3 and apolipoprotein E were fed an atherogenic diet for 16 weeks. Aortic lesions were significantly increased in double-knockout mice and mice heterozygous for PTX3 compared with apolipoprotein E-knockout mice. Mice lacking PTX3 showed a more pronounced inflammatory profile in the vascular wall as detected by cDNA microarray and quantitative polymerase chain reaction analysis and an increased macrophage accumulation within the plaque. Finally, lesion size correlated with the number of bone marrow monocytes. Conclusion-PTX3 has atheroprotective effects in mice, which, in light of the cardioprotective effects recently reported, suggests a cardiovascular protective function of the long pentraxin 3 through the modulation of the immunoinflammatory balance in the cardiovascular system. (Circulation. 2009;120:699-708.)