The alternative activation of M2 macrophages in the lungs has been implicated as a causative agent in pulmonary fibrosis; however, the mechanisms underlying M2 polarization are poorly characterized. In this study, we investigated the role of the ubiquitously expressed Src homology domain–containing tyrosine phosphatase Shp2 in this process. Shp2 inactivation augmented IL-4–mediated M2 polarization in vitro, suggesting that Shp2 regulates macrophage skewing and prevents a bias toward the M2 phenotype. Conditional removal of Shp2 in monocytes/macrophages with lysozyme M promoter–driven Cre recombinase caused an IL-4–mediated shift toward M2 polarization. Additionally, an increase in arginase activity was detected in Shp2∆/∆ mice after i.p. injection of chitin, whereas Shp2-deficient macrophages showed enhanced M2 polarization and protection against schistosome egg–induced schistosomiasis. Furthermore, mutants were more sensitive than control mice to bleomycin-induced inflammation and pulmonary fibrosis. Shp2 was associated with IL-4Rα and inhibited JAK1/STAT6 signaling through its phosphatase activity; loss of Shp2 promoted the association of JAK1 with IL-4Rα, which enhanced IL-4–mediated JAK1/STAT6 activation that resulted in M2 skewing. Taken together, these findings define a role for Shp2 in alveolar macrophages and reveal that Shp2 is required to inhibit the progression of M2-associated pulmonary fibrosis.

Hematopoietic stem cells (HSCs) produce all lineages of mature blood cells for the lifetime of an organism. In vertebrates, HSCs derive from the transition of the hemogenic endothelium (HE) in the floor of the embryonic dorsal aorta. Most recently, a series of proinflammatory factors, such as tumor necrosis factor-α, interferon-γ, and Toll-like receptor 4, have been confirmed to play a key role in HSC specification. However, the full complement of necessary signaling inputs remains unknown to date. Here, we show that interleukin-6R (IL6R) via IL6 is required and sufficient for HSC generation. We found that Notch activates IL6R by regulating its expression in the HE and in HSCs. The secretion of IL6 mainly originates from HSC-independent myeloid cells, but not from HSCs and their adjacent vascular endothelial cells. In addition, blocking IL6 signaling does not affect vascular development or the production of primitive erythrocytes. Taken together, our results uncover a previously obscure relationship between IL6 signaling and HSC production and provide new insights into HSC regeneration using proinflammatory factors in vitro.

BackgroundLung cancer in nonsmokers tends to be driven by a single somatic mutation or a gene fusion. KIF5B-RET fusion is an oncogene identified in non-small cell lung cancers. In this study, we verified the oncogenic activity of KIF5B-RET fusion and investigated how KIF5B-RET activates the specific signaling pathways for cellular transformation. We aimed to provide a basis for the further development of the therapy for KIF5B-RET positive lung cancer patients.MethodsRT-PCR was used to screen for KIF5B-RET fusions in Chinese lung cancer patients. To verify the oncogenic activity of KIF5B-RET kinase in lung cancer cells, we manipulated its expression genetically followed by colony formation and tumor formation assays. The mechanism by which KIF5B-RET kinase induces proliferation was investigated by western blot, coimmunoprecipitation, and administration of RET, MAPK and STAT3 inhibitors.ResultsOur study identified a KIF5B-RET fusion in Chinese NSCLC patients and demonstrated that KIF5B-RET transfected cells showed a significantly increased proliferation rate and colony-forming ability. Furthermore, we found that KIF5B-RET fusion kinase induced multilevel activation of STAT3 at both Tyr705 and Ser727, and KIF5B-RET-STAT3 signaling related inhibitors repressed the proliferation and tumorigenicity of lung cancer cells significantly.ConclusionsOur data suggest that KIF5B-RET promotes the cell growth and tumorigenicity of non-small cell lung cancers through multilevel activation of STAT3 signaling, providing possible strategies for the treatment of KIF5B-RET positive lung cancers.

Most ultrasonic guided wave methods focus on tone burst excitation to reduce the effect of dispersion so as to facilitate signal interpretation. However, the resolution of the output cannot attain a very high value because time duration of the excitation waveform cannot be very small. To overcome this limitation, a pulse compression technique is introduced to Lamb wave propagation to achieve a δ-like correlation so as to obtain a high resolution for inspection. Ideal δ-like correlation is impossible as only a finite frequency bandwidth can propagate. The primary purpose of this paper is to design a proper excitation waveform for Lamb wave pulse compression, which shortens the correlation as close as possible to a δ function. To achieve this purpose, the performance of some typical signals is discussed in pulse compression, which include linear chirp (L-Chirp) signal, nonlinear chirp (NL-Chirp) signal, Barker code (BC), and Golay complementary code (GCC). In addition, how the excitation frequency range influences inspection resolution is investigated. A strategy for the frequency range determination is established subsequently. Finally, an experiment is carried out on an aluminum plate where these typical signals are used as excitations at different frequency ranges. The quantitative comparisons of the pulse compression responses validate the theoretical findings. By utilizing the experimental data, the improvement of pulse compression in resolution compared with tone burst excitation is also validated, and the robustness of the waveform design method to inaccuracies in the dispersion compensation is discussed as well.