Increased neutrophil motility by beta-glucan in the absence of chemoattractant

Systemic candidasis is a life-threatening complication of antibiotic and im munosuppressive therapies and can alter host defense mechanisms through pat hways that are poorly understood. Promotion of polymorphonuclear leukocyte (PMN) chemotaxis by beta -glucan towards fMLP or IL-8 gradients demonstrate s a fundamental effect on host defenses by pathogenic fungi. The aim of the present study was to determine whether recognition of beta -glucan is suff icient to alter PMN motility in the absence of agonists of G-coupled protei n chemotactic receptors. Present findings demonstrate a profound increase i n PMN motility by beta -glucan supplementation of a fibronectin substratum in an underagarose migration assay. Motility on beta -glucan included a 3-f old increase in distance of migration, as well as a 5-fold increase in the number of PMNs recruited into the motile phase as compared to motility on f ibronectin alone. This promotion of motility is determined by the beta2 int egrin complement receptor 3 (CR3) (CD11b/CD18) rather than the beta1 integr in very late antigen 3 (VLA-3), which mediates chemotaxis on beta -glucan-s upplemented matrix towards fMLP. PMN motility on beta -glucan-supplemented fibronectin was selectively decreased by inhibitors of pp60 src and ras, wh ereas motility was promoted by inhibition of p38-MAPK. No effect of these i nhibitors was seen on PMNs migrating on fibronectin alone. Migration on bet a -glucan-supplemented fibronectin, but not on fibronectin alone, was negat ively regulated by protein kinase C (PKC) or cAMP activation. These finding s indicate that beta -glucan is sufficient to alter the migratory capacity of PMN in the absence of costimulation by fMLP. Enhanced PMN migration on b eta -glucan is mediated through specific integrins and second messenger pat hways that are distinct from those utilized by PMNs migrating in the absenc e of beta -glucan.