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Integrin Engagement Mediates the Human Polymorphonuclear Leukocyte Response to a Fungal Pathogen-Associated Molecular Pattern¹

Liz M. Lavigne^2,*,, Xian M. O’Brien^2,*,, Minsoo Kim^*, Jessie W. Janowski^*, Jorge E. Albina^* and Jonathan S. Reichner^3,*

^* Division of Surgical Research, Department of Surgery, Rhode Island Hospital and Brown University School of Medicine, Providence, RI 02903; and Graduate Program in Pathobiology, Brown University, Providence, RI 02912

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 -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, -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 -glucan is suppressed by addition of ₁ integrin ligands to the -glucan matrix. Suppression was dose dependent and steric hindrance was ruled out. ₁ integrin ligands did not affect respiratory burst to ingestible -glucan-containing particles, phorbol esters or live yeast hyphae. Furthermore, in the absence of matrix, Ab activation of VLA3 or VLA5, but not other ₁ integrins, also prevented -glucan-induced respiratory burst. 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 ₁ integrins to include modulating PMN respiratory burst to a pathogen-associated molecular pattern.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (GM-066194 (to J.S.R.) and GM-42859 (to J.E.A.)); Grant Assistance in Areas of National Need from the U.S. Department of Education (to L.M.L. and X.M.O.); the American Heart Association (0535498T (to M.K.)); and allocations to the Department of Surgery by Rhode Island Hospital.

² L.M.L. and X.M.O. contributed equally to the generation of this manuscript.

³ Address correspondence and reprint requests to Dr. Jonathan S. Reichner, Department of Surgery, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903. E-mail address: Reichner{at}Brown.edu

⁴ Abbreviations used in this paper: PMN, polymorphonuclear leukocyte; PAMP, pathogen-associated molecular pattern; ECM, extracellular matrix; Fn, fibronectin; CR3, complement receptor 3; O₂, superoxide anion; WGP, whole -glucan particle; dPBS, Dulbecco’s PBS solution.