Astrocytic transforming growth factor-beta signaling reduces subacute neuroinflammation after stroke in mice

Abstract

Astrocytes limit inflammation after CNS injury, at least partially by physically containing it within an astrocytic scar at the injury border. We report here that astrocytic transforming growth factor-beta (TGFβ) signaling is a second, distinct mechanism that astrocytes utilize to limit neuroinflammation. TGFβs are anti-inflammatory and neuroprotective cytokines that are upregulated subacutely after stroke, during a clinically accessible time window. We have previously demonstrated that TGFβs signal to astrocytes, neurons, and microglia in the stroke border days after stroke. To investigate whether TGFβ affects astrocyte immunoregulatory functions, we engineered “Ast-Tbr2DN” mice where TGFβ signaling is inhibited specifically in astrocytes. Despite having a similar infarct size to wildtype controls, Ast-Tbr2DN mice exhibited significantly more neuroinflammation during the subacute period after distal middle cerebral occlusion (dMCAO) stroke. The peri-infarct cortex of Ast-Tbr2DN mice contained over 60% more activated CD11b+ monocytic cells and twice as much immunostaining for the activated microglia and macrophage marker CD68 than controls. Astrocytic scarring was not altered in Ast-Tbr2DN mice. However, Ast-Tbr2DN mice were unable to upregulate TGF-β1 and its activator thrombospondin-1 two days after dMCAO. As a result, the normal upregulation of peri-infarct TGFβ signaling was blunted in Ast-Tbr2DN mice. In this setting of lower TGFβ signaling and excessive neuroinflammation, we observed worse motor outcomes and late infarct expansion after photothrombotic motor cortex stroke. Taken together, these data demonstrate that TGFβ signaling is a molecular mechanism by which astrocytes limit neuroinflammation, activate TGFβ in the peri-infarct cortex, and preserve brain function during the subacute period after stroke.

Monocyte-Derived Macrophages Contribute to Spontaneous Long-Term Functional Recovery after Stroke in Mice

“…Other studies have demonstrated increased expression of TGF␤ (Lehrmann et al, 1998;Martinez et al, 2001;Doyle et al, 2010;Pál et al, 2012) and its receptor (Pál et al, 2014) after stroke, mostly in macrophages (Lehrmann et al, 1998;Martinez et al, 2001;Doyle et al, 2010). TGF␤ has been shown to suppress excessive neuroinflammation during the subacute phase after brain ischemia, as evidenced by decreased expression of the proinflammatory microglia/macrophage markers CD68 and iNOS (Cekanaviciute et al, 2014), and is also able to directly inhibit LPSmediated activation of microglia (Kim et al, 2004;Le et al, 2004). Zhou et al (2012) recently demonstrated that TGF␤ enhances IL-4-induced alternative activation of microglia by strongly increasing the expression of Ym1.…”

Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke

“…Astrocytic transforming growth factor-beta (TGF-β) is anti-inflammatory and a neuroprotective cytokine that is upregulated after stroke. In mice with TGF-β signaling specifically inhibited in astrocytes, photothrombotic motor cortex stroke leads to excessive inflammation, infarct expansion and worse motor outcome (Cekanaviciute et al , 2014). These data suggest that reactive astrocytes play an essential role in neuroprotection by limiting inflammation in the peri-infarct cortex and preserve brain function during the subacute period after stroke.…”

Delayed ALK5 inhibition improves functional recovery in neonatal brain injury

“…11 TGFß, which is associated with the M2-like microglial reaction, is often regarded as an anti-inflammatory cytokine, and indeed, antagonizing TGFß signaling in models of adult stroke exacerbates lesion size. 12,13 However, other studies in the literature reveal TGFß to have a complicated and sometimes paradoxical effect upon CNS injury resolution. For example, in experimental autoimmune encephalomyelitis, inhibiting TGFb1 signaling reduced T-cell infiltration and reduced the severity of disease.…”