Galectin-3 Is Required for Resident Microglia Activation and Proliferation in Response to Ischemic Injury

Abstract

Growing evidence suggests that galectin-3 is involved in fine tuning of the inflammatory responses at the periphery, however, its role in injured brain is far less clear. Our previous work demonstrated upregulation and coexpression of galectin-3 and IGF-1 in a subset of activated/proliferating microglial cells after stroke. Here, we tested the hypothesis that galectin-3 plays a pivotal role in mediating injury-induced microglial activation and proliferation. By using a galectin-3 knock-out mouse (Gal-3KO), we demonstrated that targeted disruption of the galectin-3 gene significantly alters microglia activation and induces ϳ4-fold decrease in microglia proliferation. Defective microglia activation/proliferation was further associated with significant increase in the size of ischemic lesion, ϳ2-fold increase in the number of apoptotic neurons, and a marked deregulation of the IGF-1 levels. Next, our results revealed that contrary to WT cells, the Gal3-KO microglia failed to proliferate in response to IGF-1. Moreover, the IGF-1-mediated mitogenic microglia response was reduced by N-glycosylation inhibitor tunicamycine while coimmunoprecipitation experiments revealed galectin-3 binding to IGFreceptor 1 (R1), thus suggesting that interaction of galectin-3 with the N-linked glycans of receptors for growth factors is involved in IGF-R1 signaling. While the canonical IGF-1 signaling pathways were not affected, we observed an overexpression of IL-6 and SOCS3, suggesting an overactivation of JAK/STAT3, a shared signaling pathway for IGF-1/IL-6. Together, our findings suggest that galectin-3 is required for resident microglia activation and proliferation in response to ischemic injury.

Resident microglia, rather than blood‐derived macrophages, contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia‐ischemia

“…This is consistent with our findings, but we could further identify the resident microglia as primarily responsible for this difference between the immature and the adult brain. Galectin‐3 has been reported to be produced by activated microglia/macrophages after HI and to be required for resident microglia activation response to HI (Burguillos et al, 2015; Lalancette‐Hébert et al, 2012; Yan et al, 2009). We have previously shown that galectin‐3‐positive microglia is detectable only in areas with overt brain injury (Li et al, 2011).…”

Role of neuroinflammation in ischemic stroke

“…[83][84][85] Several reports have demonstrated that defective microglial activation increased the infarction and apoptosis after ischemic stroke. [86] Microglial activation following ischemic stroke can promote activated microglia to migrate toward the ischemic hemisphere of the cerebral cortex. [87] It is suggested that active microglia have predominantly harmful effects in the acute stages of ischemic stroke and most beneficial effects appear in delayed stages.…”

Histological Mapping and Subtype-Specific Functions of Galectins in Health and Disease

“…In models of focal brain ischemia and stroke, galectin-1 and -3 were found to be upregulated in astrocytes and microglial cells, respectively (35)(36)(37)(38).…”

“…Although the precise functions of galectins under ischemic conditions remain unclear, galectin-1 and -3 may improve the functional recovery of the damaged brain tissues (37,38). Galectin-1, -3, and -9 are strongly expressed in mesenchymal stem cells derived from bone marrow and umbilical cord blood (44)(45)(46)(47).…”