Integrin engagement mediates the human polymorphonuclear leukocyte response to a fungal pathogen-associated molecular pattern.
Extravasation of leukocytes from peripheral blood is required for an effective inflammatory response at sites of tissue infection. Integrins help mediate extravasation and navigate the leukocyte to the infectious source. A novel role for integrins in regulating the effector response to a cell wall component of fungal pathogens is the subject of the current study. Although phagocytosis is useful for clearance of unicellular fungi, the immune response against large, noningestible hyphae is not well-understood. Fungal beta-glucan, a pathogen-associated molecular pattern, activates production of superoxide anion in leukocytes without the need for phagocytosis. To model polymorphonuclear leukocyte (PMN) recognition of fungi under conditions in which phagocytosis cannot occur, beta-glucan was covalently immobilized onto tissue culture plastic. Plasma membrane-associated respiratory burst was measured by reduction of ferricytochrome C. Results show that the human PMN oxidative burst response to immobilized beta-glucan is suppressed by addition of beta(1) integrin ligands to the beta-glucan matrix. Suppression was dose dependent and steric hindrance was ruled out. beta(1) integrin ligands did not affect respiratory burst to ingestible beta-glucan-containing particles, phorbol esters or live yeast hyphae. Furthermore, in the absence of matrix, Ab activation of VLA3 or VLA5, but not other beta(1) integrins, also prevented beta-glucan-induced respiratory burst. beta(1)-induced suppression was blocked and burst response restored by treating neutrophils with either the cell-binding fragment of soluble human Fn, cyclic RGD peptide, or Ab specific to VLA3 or VLA5. Together these findings extend the functional role of beta(1) integrins to include modulating PMN respiratory burst to a pathogen-associated molecular pattern.
Lavigne
Liz M
LM
Division of Surgical Research, Department of Surgery, Rhode Island Hospital and Brown University School of Medicine, Providence, RI 02903, USA.
O'Brien
Xian M
XM
Kim
Minsoo
M
Janowski
Jessie W
JW
Albina
Jorge E
JE
Reichner
Jonathan S
JS
D002176:Candida albicans / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002473:Cell Wall / Q000276:immunology / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism / Q000502:physiology; D005353:Fibronectins / Q000502:physiology; D006801:Humans; D025301:Hyphae / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D039201:Integrin alpha3beta1 / Q000378:metabolism / Q000502:physiology; D039081:Integrin alpha5beta1 / Q000378:metabolism / Q000502:physiology; D039641:Integrin beta Chains / Q000378:metabolism* / Q000502:physiology; D009504:Neutrophils / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D010084:Oxidation-Reduction; D016897:Respiratory Burst / Q000276:immunology; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism; D047071:beta-Glucans / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D039201:Integrin alpha3beta1; D039081:Integrin alpha5beta1; D039641:Integrin beta Chains; D047071:beta-Glucans; D013481:Superoxides