Myeloid PTEN Deficiency Protects Livers from Ischemia Reperfusion Injury by Facilitating M2 Macrophage Differentiation

Abstract

Although roles of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in regulating cell proliferation are well established, its function in immune responses remains to be fully appreciated. In the current study, we analyzed myeloid-specific PTEN function in regulating tissue inflammatory immune response in a murine liver partial warm ischemia model. Myeloid-specific PTEN knock-out (KO) resulted in liver protections from ischemia reperfusion injury (IRI) by deviating local innate immune response against IR toward the regulatory type: expressions of pro-inflammatory genes were selectively decreased and anti-inflammatory IL-10 was simultaneously increased in IR livers of PTEN KO mice, as compared with those of wild-type (WT) mice. PI3 kinase inhibitor and IL-10 neutralizing Abs, but not exogenous LPS, recreated liver IRI in these KO mice. At the cellular level, Kupffer cells, as well as peritoneal macrophages, isolated from KO mice expressed higher levels of M2 markers, and produced lower TNF-α and higher IL-10 in response to TLR ligands, than their WT counterparts. They had enhanced Stat3 and Stat6, but diminished Stat1 signaling pathway activations in response to TLR4 stimulation. Inactivation of KCs by gadolinium chloride enhanced pro-inflammatory immune activation and increased IRI in livers of myeloid PTEN KO mice. Thus, myeloid PTEN deficiency protects livers from IRI by facilitating M2 macrophage differentiation.

Hyperglycemia and Liver Ischemia Reperfusion Injury: A Role for the Advanced Glycation Endproduct and Its Receptor Pathway

“…Kupffer cells (KCs) were isolated as previously described (24). In brief, livers were perfused in situ via the portal vein with calcium-and magnesium-free HBSS supplemented with 2% heat-inactivated FBS, followed by 0.27% collagenase IV (Sigma, St. Louis, MO).…”

IFN-γ Primes Macrophage Activation by Increasing Phosphatase and Tensin Homolog via Downregulation of miR-3473b

“…Macrophages are important immune effector cells whose activation is tightly regulated (8,9). IL-10 production is one important suppressor loop for macrophage activation in immune response (10).…”

Phosphatase regulation of macrophage activation

“…Consistent with an M(IL-4)-like activation state, PTEN deficient mice have increased susceptibility to Streptococcus pneumonia infection during which their macrophages produce lower levels of pro-inflammatory TNF and increased antiinflammatory IL-10 relative to wild type mice [51]. Myeloid PTEN deficiency also protects mice from ischemia reperfusion injury, which is associated with increased M(IL-4) macrophage markers, reduced production of pro-inflammatory cytokines, and increased production of IL-10 [52]. Importantly, the protective effect was reversible by inhibition of PI3K suggesting that PTEN-mediated protection was due to its effects reducing PI3K-Akt signalling [52].…”

“…Myeloid PTEN deficiency also protects mice from ischemia reperfusion injury, which is associated with increased M(IL-4) macrophage markers, reduced production of pro-inflammatory cytokines, and increased production of IL-10 [52]. Importantly, the protective effect was reversible by inhibition of PI3K suggesting that PTEN-mediated protection was due to its effects reducing PI3K-Akt signalling [52]. In the same vein, the histone deacteylase (HDAC) inhibitor, Scriptaid, protects mice from white matter injury and, in vitro, this was demonstrated to be due to inactivation of PTEN, which polarizes microglia toward an anti-inflammatory activation state via increased PI3K/Akt activity [53].…”