αMβ₂ integrin activation prevents alternative activation of human and murine macrophages and impedes foam cell formation.
BACKGROUND
The alternative activation of monocytes by interleukin (IL)-13 and IL-4 is a significant component of the inflammatory response. The consequences of alternative activation in inflammatory diseases remain to be determined.


OBJECTIVE
In this report, we explored how integrins, receptors important for monocyte migration to inflammatory sites, regulate IL-13-mediated monocyte activation. We focused on the analysis of 2 proteins, which are upregulated during the alternative activation and are important for the development of atherosclerosis, an oxidative enzyme 15-lipoxygenase (15-LO) and a scavenger receptor CD36.


RESULTS
We found that adhesion of resting monocytes through β(2) integrins and inside-out activation of β(2) integrins by monocyte chemoattractant protein-1 did not change IL-13-stimulated 15-LO upregulation; however, preincubation of monocytes with the antibody MEM48, which generates full activation of β(2) integrins, significantly inhibited 15-LO mRNA and protein expression. In contrast, activation of β(1) integrins had no effect on 15-LO expression. Analysis of integrin clustering through α(M), α(L), α(X), and α(D) subunits demonstrated the pivotal role for integrin α(M)β(2) in inhibiting 15-LO expression. IL-13 treatment upregulates 15-LO-dependent CD36 expression on human monocytes; our studies showed that β(2) integrin activation and α(M) integrin clustering significantly inhibited IL-13-dependent CD36 mRNA and protein expression, as well as CD36-related foam cell formation. Moreover, IL-13 stimulation of α(M)-deficient peritoneal macrophages demonstrated an upregulated level of 15-LO induction, CD36 expression, and lipid accumulation as compared with wild-type controls.


CONCLUSIONS
The adhesion of monocytes/macrophages through activated integrin α(M)β(2) has a regulatory and potential atheroprotective function during the alternative activation of macrophages.
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA. yakubv@ccf.org
Valentin P
VP
Yakubenko
Ashish
A
Bhattacharjee
Elzbieta
E
Pluskota
Martha K
MK
Cathcart
D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005487:Foam Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D037181:Lectins, C-Type / Q000378:metabolism; D008262:Macrophage Activation / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D010446:Peptide Fragments / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism
D039481:CD11b Antigen; D018955:CD36 Antigens; C548810:CD36 protein (93-110); D018793:Interleukin-13; D037181:Lectins, C-Type; D016177:Macrophage-1 Antigen; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D001093:Arachidonate 15-Lipoxygenase
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