From Macrophage Interleukin-13 Receptor to Foam Cell Formation

Abstract

Background: CD36, a macrophage receptor critical for oxidized lipid uptake during atherogenesis, is up-regulated after IL-4/IL-13 stimulation. Results: The mechanism whereby integrin ␣ M ␤ 2 inhibits CD36 gene expression and related foam-cell formation is elucidated. Conclusion: Activated integrin ␣ M ␤ 2 suppresses CD36-mediated lipid uptake by blocking Tyk2-and Jak2-mediated signaling pathways. Significance: ␣ M ␤ 2 integrin regulation of CD36 expression and function reveals a new mechanism that may control atherogenesis.

Quantitative proteomics analyses of activation states of human THP-1 macrophages

“…They form a cell surface receptor (integrin α M ß 2 ) that mediates phagocytosis, migration and chemotaxis [41]. In addition, talin and cysteine proteinase cathepsin X/Z (CTSZ) were also up-regulated in IL4-stimulated macrophages.…”

Mac-1 Regulates IL-13 Activity in Macrophages by Directly Interacting with IL-13Rα1

“…Co-evolution between Mac-1 and IL-13R␣1-Recently, Yakubenko et al (9,14) reported that Mac-1 suppresses IL-13-induced JAK/STAT activation in macrophages and reduces their uptake of oxLDL in vitro; however, the molecular mechanism underlying this unique regulatory function of Mac-1 is not yet established. To identify potential biological partners that confer the inhibitory activity of Mac-1 toward IL-13-induced macrophage activation, we used an unbiased informatics-based method, termed Mirrortree (28 -30), to predict protein-protein interactions.…”

“…Recent studies demonstrated that Mac-1, a major leukocyte integrin expressed on macrophages and macrophage-derived foam cells, exhibits potent inhibitory activities toward JAK/STAT activation in IL-13-stimulated macrophages, which reduces their ability to uptake oxLDL in vitro (9,14). However, the molecular mechanism by which Mac-1 inhibits IL-13 signaling in macrophages is still unknown.…”

“…For example, Mac-1 binding of C3bi has been shown to suppress inflammation and induce immune tolerance (41,42); on the other hand, Mac-1-mediated adhesion to fibrin exacerbates inflammatory diseases (36,39). Given the suppressive activity of Mac-1 toward IL-13 signaling in macrophages (9,14), we sought in this work to identify candidate partners of Mac-1 that mediate this unique regulatory activities. To achieve our objective, we developed a computational method to predict protein- protein interactions, based in part on Mirrortree, using the entire genetic and protein sequence database.…”

“…Indeed, AAMs are found to produce high levels of 15-LO and CD36 under the pathological setting of hyperlipidemia (2,9,10) and are thus more susceptible to foam cell transformation than classically activated macrophages (11,12). Recently, Yakubenko et al (9,14) reported * This work was supported by National Institute of Health Grants NHLBI that integrin Mac-1 (CD11b/CD18 or ␣ M ␤ 2 ) functions to suppress IL-13-induced JAK/STAT activation in macrophages and reduces their uptake of oxLDL in vitro, suggesting that Mac-1 plays a regulatory role in foam cell development. However, the molecular mechanism by which Mac-1 inhibits IL-13-induced JAK/STAT activation in macrophages is unknown.…”