Cells exposed to sublethal oxidative stress selectively attract monocytes/macrophages via scavenger receptors and MyD88-mediated signaling.
The innate immune system responds to endogenous molecules released during cellular stress or those that have undergone modifications normally absent in healthy tissue. These structures are detected by pattern-recognition receptors, alerting the immune system to "danger." In this study, we looked for early signals that direct immune cells to cells undergoing stress before irreversible damage takes place. To avoid detecting signals emanating from apoptotic or necrotic cells we exposed fibroblasts to sublethal oxidative stress. Our results indicate that both nonenzymatic chemical reactions and aldehyde dehydrogenase-2-mediated enzymatic activity released signals from fibroblasts that selectively attracted CD14(+) monocytes but not T, NK, and NKT cells or granulocytes. Splenocytes from MyD88(-/-) mice did not migrate, and treatment with an inhibitory peptide that blocks MyD88 dimerization abrogated human monocyte migration. Monocyte migration was accompanied by downmodulation of CD14 expression and by the phosphorylation of IL-1R-associated kinase 1, a well-known MyD88-dependent signaling molecule. The scavenger receptor inhibitors, dextran sulfate and fucoidan, attenuated monocyte migration toward stressed cells and IL-1R-associated kinase 1 phosphorylation. Surprisingly, although monocyte migration was MyD88 dependent, it was not accompanied by inflammatory cytokine secretion. Taken together, these results establish a novel link between scavenger receptors and MyD88 that together function as sensors of oxidation-associated molecular patterns and induce monocyte motility. Furthermore, the data indicate that MyD88 independently regulates monocyte activation and motility.
Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, 91120 Jerusalem, Israel.
Anat
A
Geiger-Maor
Inbar
I
Levi
Sharona
S
Even-Ram
Yoav
Y
Smith
Dawn M
DM
Bowdish
Gabriel
G
Nussbaum
Jacob
J
Rachmilewitz
D000444:Aldehyde Dehydrogenase; D000818:Animals; D002465:Cell Movement; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D018950:Lipopolysaccharide Receptors; D008264:Macrophages; D051379:Mice; D009000:Monocytes / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D051116:Receptors, Scavenger / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
D018950:Lipopolysaccharide Receptors; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051116:Receptors, Scavenger; D000444:Aldehyde Dehydrogenase