Figure 4

The cytokine network of Wallerian degeneration. Injury sets in motion the cytokine network of normal Wallerian degeneration. Intact myelinating Schwann cells enwrap intact axons and further express normally the inflammatory cytokines TNFα and IL-1α mRNAs and the TNFα protein. Traumatic injury at a distant site in the far left (not shown) induces the rapid upregulation of TNFα and IL-1α mRNAs expression and proteins production and secretion by Schwann cells within 5 hours. The nature of the signal(s) that are initiated at the injury site, travel down the axon, and then cross over to Schwann cells are not known (?). Concomitantly, Schwann cell derived TNFα and IL-1α induce resident fibroblasts to upregulate the expression of cytokines IL-6 and GM-CSF mRNAs and the production and secretion of their proteins within 2 to 5 hours after the injury. Inflammatory IL-1β mRNA expression and protein production and secretion are induced in Schwann cells with a delay of several hours. The expression of chemokines MCP-1/CCL2 and MIP-1α/CCL3 are upregulated by TNFα, IL-1β and IL-6 as of day 1 after the injury in Schwann cells, and possibly also in fibroblasts and endothelial cells. In turn, circulating monocytes begin their transmigration into the nerve tissue 2 to 3 days after the injury. Fibroblasts begin producing apolipoprotein-E (apo-E) and Schwann cells Galectin-3/MAC-2 (Gal-3) just before the onset of monocyte recruitment. Apolipoprotein-E and Galectin-3/MAC-2 may drive monocyte differentiation towards M2 phenotype macrophage which further produces apolipoprotein-E and Galectin-3/MAC-2. Macrophages efficiently produce IL-10 and IL-6 and much less TNFα, IL-1α, IL-1β. The anti-inflammatory cytokine IL-10, aided by IL-6, down-regulates productions of cytokines. Schwann cells and fibroblasts produce also LIF. Arrows indicate activation and broken lines down-regulation. Not all possible interactions and molecules produced are shown (e.g. autocrine interactions and the role of GM-CSF inhibitor); see text for additional information. The break-down of axons and myelin, and their phagocytosis are not illustrated here; see, however, Figure 1 and Figure 2.