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Tissue-resident macrophages constitute heterogeneous populations with unique functions and distinct gene-expression signatures. While it has been established that they originate mostly from embryonic progenitor cells, the signals that induce a characteristic tissue-specific differentiation program remain unknown. We found that the nuclear receptor PPAR-γ determined the perinatal differentiation and identity of alveolar macrophages (AMs). In contrast, PPAR-γ was dispensable for the development of macrophages located in the peritoneum, liver, brain, heart, kidneys, intestine and fat. Transcriptome analysis of the precursors of AMs from newborn mice showed that PPAR-γ conferred a unique signature, including several transcription factors and genes associated with the differentiation and function of AMs. Expression of PPAR-γ in fetal lung monocytes was dependent on the cytokine GM-CSF. Therefore, GM-CSF has a lung-specific role in the perinatal development of AMs through the induction of PPAR-γ in fetal monocytes.

This overview of the 4th edition of the WHO Classification of thymic tumors has two aims. First, to comprehensively list the established and new tumour entities and variants that are described in the new WHO Classification of thymic epithelial tumors, germ cell tumors, lymphomas, dendritic cell and myeloid neoplasms, and soft tissue tumors of the thymus and mediastinum; second, to highlight major differences in the new WHO Classification that result from the progress that has been made since the 3rd edition in 2004 at immunohistochemical, genetic and conceptual levels. Refined diagnostic criteria for type A, AB, B1–B3 thymomas and thymic squamous cell carcinoma are given and will hopefully improve the reproducibility of the classification and its clinical relevance. The clinical perspective of the classification has been strengthened by involving experts from radiology, thoracic surgery and oncology; by incorporating state-of-the-art PET/CT images; and by depicting prototypic cytological specimens. This makes the thymus section of the new WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart a valuable tool for pathologists, cytologists and clinicians alike. The impact of the new WHO Classification on therapeutic decisions is exemplified in this overview for thymic epithelial tumors and mediastinal lymphomas, and future perspectives and challenges are discussed.

Objective-Sepsis is a major cause of death for intensive care patients. High concentrations of inflammatory cytokines are characteristic of severe systemic inflammation and activated monocytes are their predominant cellular source. To identify targets for antiinflammatory intervention, we investigated the response of human macrophages to inflammatory and antiinflammatory mediators. Methods and Results-We profiled gene expression in human macrophages exposed to lipopolysaccharide (LPS) and interferon (IFN)-␥ in the presence or absence of recombinant activated protein C (APC) or IL-10 and identified Wnt5A as one of the transcripts most highly induced by LPS/IFN-␥ and suppressed by APC and IL-10. We confirmed regulation of Wnt5A protein in macrophages and detected it in sera and bone marrow macrophages of patients with severe sepsis. We established that a functional Wnt5A/frizzled-5/CaMKII signaling pathway was essential for macrophage inflammatory activation. To prove the essential contribution of Wnt5A we measured inflammatory cytokines after stimulation with Wnt5A, silenced Wnt5A by siRNA, and blocked receptor binding with soluble Frizzled-related peptide-1 (sFRP1). Key Words: geneexpression Ⅲ macrophages Ⅲ activated protein C S epsis is a suspected or proven infection with a systemic inflammatory response. In severe sepsis, organ dysfunction also occurs and it is associated with a high mortality and morbidity. Severe sepsis still causes about 9.3% of all deaths in the USA. 1,2 Conclusion-Wnt5A is critically involved in inflammatory macrophage See accompanying article on page 400During sepsis, the extent of plasma protein C depletion correlates with the severity of the outcome. 3 In animal studies 4 and clinical trials APC prevented death from severe sepsis or septic shock. 5 Although this beneficial effect of APC is mostly ascribed to its anticoagulant properties, antiinflammatory effects of APC have also been proposed. 6 The direct modulation of inflammation by APC has recently been described in gene expression profiling studies with human endothelial cells. 7,8 Recently, recombinant human APC has been introduced as a therapeutic agent for treatment of patients with severe sepsis because of its unique anticoagulant and antiinflammatory properties; however, the exact mechanism of antiinflammatory action is still unknown. 9 Macrophages play a central role in inflammation by responding to and releasing of numerous inflammatory cytokines and chemokines, leading to severe systemic inflammation and septic shock. However, the knowledge of antiinflammatory interactions on the level of monocytes/macrophages is scant. Therefore, we decided to expand our investigations on antiinflammatory effects of APC on this cellular system. In the present study, we were using a whole genome expression analysis approach, to define novel targets of APC in an in vitro model of inflammatory macrophage activation. Using probes obtained from human macrophages stimulated by INF-␥ (IFN-␥) and endotoxin (LPS), we consistently found Wnt5A to ...

Interleukin-1␣ (IL-1␣