Myeloid PTEN Deficiency Protects Livers From Ischemia Reperfusion Injury By Facilitating M2 Macrophage Development.

Abstract

Background & Aims Although roles of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in regulating cell proliferation are well established, its function in regulating immune responses remains to be fully appreciated. Methods By crossing Lyz-Cre and PTEN-LoxP mice, we created myeloid-specific PTEN knock-out (KO) mice and studied PTEN function in regulating tissue inflammatory immune response in a murine liver partial warm ischemia model. Results Complete, but not haploid, myeloid-specific PTEN 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, including TNF-a, IL-6, IL-1b, IL-12p40 and CXCL10, were selectively decreased and anti-inflammatory IL-10 gene expression was simultaneously increased in IR livers of PTEN KO mice, as compared with those of wild-type (WT) mice IL-10 neutralizing Abs, but not exogenous LPS, recreated liver IRI in these KO mice.Figure: No Caption available.Figure: No Caption available.At the cellular level, Kupffer cells isolated from KO mice expressed higher levels of M2 markers, CD206 and CD301, and produced lower TNF-a and higher IL-10 in response to TLR ligands in vitro, than their WT counterparts. Furthermore, PTEN KO macrophages had enhanced Stat3 and Stat6, but diminished Stat1, activation in response to TLR4 stimulation. In sharp contrast to its effect in WT mice, gadolinium chloride which inactivated KCs enhanced liver pro-inflammatory immune activation and exaggerated IRI in myeloid PTEN KO mice. Conclusion Myeloid PTEN deficiency protects livers from IRI by facilitating M2 macrophage development.