Galectin‐3/MAC‐2, Ras and PI3K activate complement receptor‐3 and scavenger receptor‐AI/II mediated myelin phagocytosis in microglia

Abstract

The removal of degenerated myelin is essential for repair in Wallerian degeneration that follows traumatic injury to axons and in autoimmune demyelinating diseases (e.g., multiple sclerosis). Microglia can remove degenerated myelin through phosphatidylinositol-3-kinase (PI3K)-dependent phagocytosis mediated by complement receptor-3 (CR3/MAC-1) and scavenger receptor-AI/II (SRAI/II). Paradoxically, these receptors are expressed in microglia after injury but myelin is not phagocytosed. Additionally, Galectin-3/MAC-2 is expressed in microglia that phagocytose but not in microglia that do not phagocytose, suggesting that Galectin-3/MAC-2 is instrumental in activating phagocytosis. S-trans, trans-farnesylthiosalicylic (FTS), which inhibits Galectin-3/MAC-2 dependent activation of PI3K through Ras, inhibited phagocytosis. K-Ras-GTP levels and PI3K activity increased during normal phagocytosis and decreased during FTS-inhibited phagocytosis. Galectin-3/MAC-2, which binds and stabilizes active Ras, coimmunoprecipitated with Ras and levels of the coimmunoprecipitate increased during normal phagocytosis. A role for Galectin-3/MAC-2 dependent activation of PI3K through Ras, mostly K-Ras, is thus suggested. An explanation may thus be offered for deficient phagocytosis by microglia that express CR3/MAC-1 and SRAI/II without Galectin-3/MAC-2 and efficient phagocytosis when CR3/MAC-1 and SRAI/II are co-expressed with Galectin-3/MAC-2.

Glaucomatous optic nerve injury involves early astrocyte reactivity and late oligodendrocyte loss

“…It is unlikely that the Mac-2 labeling was due to the influx of macrophages since Mac-2 only labels proliferating resident microglia and does not label infiltrating peripheral macrophages after ischemic injury (Lalancette-H ebert et al, 2007). Our findings of late microglia activation using Mac-2 are consistent with studies showing that Galectin3/Mac-2 is expressed in activated microglia that phagocytose degenerated myelin in order to repair and minimize damage (Reichert and Rotshenker, 1996;Rotshenker et al, 2008). However, since aged C5BL/6J mice also showed a marked increased of Mac-2 labeling in microglia, and previous studies have described increased microglia activation due to normal aging (Chan-Ling et al, 2007;Conde and Streit, 2006), it is difficult to ascertain what fraction of the late microglia activation within the myelinated portion of the DBA/2J ON was disease-related rather than age-related.…”

“…Only one such marker, macrophage galactose-specific lectin-2 (Mac-2) was found to undergo a marked change in expression in aged DBA/2J. Mac-2 has been shown to have markedly increased expression in microglia that phagocytose myelin (Rotshenker et al, 2008(Rotshenker et al, , 2009). Cells expressing Mac-2 in the myelinated portion of the ON were confirmed to be microglia based on co-localization with Iba-1 (Supp.…”

The Role of Galectin-3/MAC-2 in the Activation of the Innate-Immune Function of Phagocytosis in Microglia in Injury and Disease

“…First, the in vivo and in vitro correlations between Galectin-3/MAC-2 expression in and myelin phagocytosis by macrophages and microglia (see above). Second, the role of PI3K in activating myelin phagocytosis; inhibition of PI3K activity resulted in the inhibition of myelin phagocytosis in macrophages and microglia (Cohen et al 2006;Makranz et al 2004;Rotshenker et al 2008). Third, the preferential activation of PI3K by K-Ras-GTP, the active form of K-Ras, which Galectin-3/MAC-2 stabilizes; stabilization follows the formation of a complex between Galectin-3/MAC-2 and K-Ras-GTP (Ashery et al 2006).…”

Extrinsic cellular and molecular mediators of peripheral axonal regeneration

“…However, IL-10 secretion within the distal stump effectively does not increase until the recruited macrophages enter the distal nerve fragment (Be'eri et al 1998), showing a peak at 7 days post-injury. GM-CSF up-regulates the lectin Galectin-3/MAC2 in Schwann cells and macrophages of the distal fragment (Narciso et al 2009;Rotshenker et al 2008;Saada et al 1996) and contributes to the proinflammatory phase of Wallerian degeneration, which is characterized most notably by increased expression of IL-1α/ß, TNFα and IL-6 as well as GM-CSF. About 7 days after injury, a GM-CSF-inhibiting molecule is produced (Mirski et al 2003), while increased amounts of IL-10 simultaneously restrict the pro-inflammatory impact of GM-CSF.…”