The role of miR-27b and PPARgamma expression during sepsis

尽管进行了深入的研究，脓毒症仍然是重症监护病房死亡的主要原因之一。脓毒症起源于最初的高炎症阶段，其特征是主要由巨噬细胞(MΦ)不受控制地释放促炎介质。缩短这一阶段将限制这种压倒性的反应，并伴随着改善败血症的结局。炎症反应通常与抗炎因子过氧化体增殖物激活受体(PPARγ)的表达减少有关，我们最近将其归因于体外培养的MF中miR-27b依赖的mR-NA的降解。我们假设脓毒症时PPARγ的表达减少，维持PPARγ的表达将通过重新激活内源性抗炎特性来维持限制性免疫反应，从而改善脓毒症的预后。利用小鼠盲肠多菌体结扎穿孔脓毒症模型，我们将阐明以下问题：1)在盲肠结扎穿孔过程中，哪种分子机制降低了M-Φ中PPARγ的表达？2)阻断这一信号通路是否维持了盲肠结扎穿孔过程中M-Φ中PPARγ的表达，从而改善了脓毒症的预后？3)相应地，过继转移稳定转导PPARγ的M-Φ是否可以改善CLP诱导的脓毒症结局？

Despite intensive research, sepsis remains one major cause of death in intensive care units. Sepsis originates from an initial hyper-inflammatory phase, characterized by the uncontrolled release of proinflammatory mediators mainly by macrophages (MΦ). Diminishing this phase would limit this overwhelming response and concomitantly improve septic outcome. Inflammatory responses are often associated with decreased expression of the anti-inflammatory factor peroxisome proliferatoractivated receptorg (PPARγ), which we recently attributed to miR-27b-dependent mRNA degradation in MF in vitro. We hypothesize that PPARγ expression is reduced in sepsis and that maintaining PPARγ expression will perpetuate a confined immune response by reactivating endogenous antiinflammatory properties thus, improving sepsis outcome. Using the murine polymicrobial cecal ligation and puncture (CLP) sepsis model, we will clarify the following questions: 1) Which molecular mechanism decreases PPARγ expression in MΦ during CLP? 2) Does blockade of this signaling pathway maintain PPARγ expression in MΦ during CLP and thus, improves sepsis outcome? 3) Accordingly, will adoptive transfer of MΦ stably transduced with a PPARγ expression construct lacking regulatory 3´-sequences improve septic outcome induced by CLP?