Sustained anti-inflammatory effects of TGF-β1 on microglia/macrophages

Abstract

Ischemic brain injuries caused release of damage-associated molecular patterns (DAMPs) that activate microglia/macrophages (MG/MPs) by binding to Toll-like receptors. Using middle cerebral artery transiently occluded rats, we confirmed that MG/MPs expressed inducible nitric oxide synthase (iNOS) on 3days after reperfusion (dpr) in ischemic rat brain. iNOS expression almost disappeared on 7dpr when transforming growth factor-β1 (TGF-β1) expression was robustly increased. After transient incubation with TGF-β1 for 24h, rat primary microglial cells were incubated with lipopolysaccharide (LPS) and released NO level was measured. The NO release was persistently suppressed even 72h after removal of TGF-β1. The sustained TGF-β1 effects were not attributable to microglia-derived endogenous TGF-β1, as revealed by TGF-β1 knockdown and in vitro quantification studies. Then, boiled supernatants prepared from ischemic brain tissues showed the similar sustained inhibitory effects on LPS-treated microglial cells that were prevented by the TGF-β1 receptor-selective blocker SB525334. After incubation with TGF-β1 for 24h and its subsequent removal, LPS-induced phosphorylation of IκB kinases (IKKs), IκB degradation, and NFκB nuclear translocation were inhibited in a sustained manner. SB525334 abolished all these effects of TGF-β1. In consistent with the in vitro results, phosphorylated IKK-immunoreactivity was abundant in MG/MPs in ischemic brain lesion on 3dpr, whereas it was almost disappeared on 7dpr. The findings suggest that abundantly produced TGF-β1 in ischemic brain displays sustained anti-inflammatory effects on microglial cells by persistently inhibiting endogenous Toll-like receptor ligand-induced IκB degradation.

Comparison of the detrimental features of microglia and infiltrated macrophages in traumatic brain injury: A study using a hypnotic bromovalerylurea

“…BU did not affect the expression of TGFβ1, which has an ameliorative action in ischemic and hemorrhagic brains (Taylor et al, ; Wattananit et al, ). TGFβ1 inhibits TLR ligands‐induced phosphorylation of IκB kinase in a sustained manner, leading to the sustained inhibition of NFκB translocation into the nucleus (Islam et al, ). This action may be correlated with the induction of anti‐inflammatory macrophage and microglia phenotypes in the subacute phase of severely damaged brain tissues (Islam et al, ; Taylor et al, ).…”

Pre- and Neonatal Exposure to Lead (Pb) Induces Neuroinflammation in the Forebrain Cortex, Hippocampus and Cerebellum of Rat Pups

“…An increase in the production of this cytokine occurs in the course of many brain diseases. For example, on the 7th day after ischemia there is an increase in TGF-β1 production, which controls disease progression and reduces the negative effects of the associated neuroinflammation [101,102]. A similar mechanism occurs in Alzheimer's disease [93,94], when the increased production of TGF-β protects the brain from excessively rapid progression of this neurodegenerative disease.…”

Favorable and unfavorable roles of microglia and macrophages in the pathologic central nervous system

“…TGFβ1 suppresses iNOS expression by LPS-treated primary rat microglia almost completely in culture at both mRNA and protein levels. The inhibitory effect of TGFβ1 is as strong as is 100 nM of Dex in culture experiments [72] . As mentioned above, once incubated with TGFβ1, LPS cannot induce NFkB translocation into nuclei in microglia.…”

“…DAMPs cause proinflammatory activation of microglia as lipopolysaccharide (LPS). However, expression of proinflammatory cytokine by both microglia and macrophages in the ischemic brain is not very remarkable [72] . TLR ligands strongly induce expression of inducible nitric oxide synthase (iNOS) by microglia in culture.…”

“…TGFβ1 may be the most abundantly released cytokine from microglia and macrophages in severely damaged brains [27,72] . TGFβ1 suppresses iNOS expression by LPS-treated primary rat microglia almost completely in culture at both mRNA and protein levels.…”