Neutrophil extravasation, a critical component of innate immunity must be tightly regulated to prevent inadvertent or prolonged inflammation and subsequent tissue damage. We have shown previously that endothelial ERK1/2 signaling essential for neutrophil transendothelial migration is induced by a soluble factor produced by activated neutrophils. In this study, we demonstrate that the soluble neutrophil factor is a truncated form of annexin A1 (AnxA1) that can be generated by calpain 1 cleavage of the N terminus, thus identifying a novel proinflammatory function to AnxA1. In contrast, neither the full-length protein nor the N-terminal 26 aa peptide, previously shown to be antiinflammatory, were able to activate Erk. Our data suggest that two different fragments of AnxA1 have opposing functions in inflammation. We also provide evidence that C-terminal AnxA1 functions by increasing ICAM1 clustering around adherent neutrophils to anchor them to the endothelium and promote transmigration through the transcellular route.

No abstract

The serum levels of alpha2-macroglobulin have been measured in normal men and mice and in a number of immunopathological conditions. Normal human concentrations are high in youth, reach their minimum in middle age, and gradually increase with old age. In all age groups the mean is higher in the female than in the male. Conversely, in normal mice the alpha2M level is low in youth, maximum in middle age, and shows a slight depression with old age, and the levels are frequently higher in males than in females; there are also strain variations. In human immunopathological conditions, there are some deviations from the normal alpha2M level but these are seen to be changes from the normal distribution of values around the mean, rather than significant elevation or depression of mean values. In some disease states studied there are differences between the sexes in the deviation from normal. "Abnormal" strains of mice had alpha2M levels within the range exhibited by "normal" mice but changes in the levels are seen in mice with various myelomas.