The transcription factor PU.1 promotes alternative macrophage polarization and asthmatic airway inflammation

The transcription factor PU.1 is involved in regulation of macrophage differentiation and maturation.However,the role of PU.1 in alternatively activated macrophage(AAM)and asthmatic inflammation has yet been investigated.Here we report that PU.1 serves as a critical regulator of AAM polarization and promotes the pathological progress of asthmatic airway inflammation.In response to the challenge of DRA(dust mite,ragweed,and Aspergillus)allergens,conditional PU.1-deficient(PU/ER(T)^(+/-))mice displayed attenuated allergic airway inflammation,including decreased alveolar eosinophil infiltration and reduced production of IgE,which were associated with decreased mucous glands and goblet cell hyperplasia.The reduced asthmatic inflammation in PU/ER(T)^(+/-) mice was restored by adoptive transfer of IL-4-induced wild-type(WT)macrophages.Moreover,after treating PU/ER(T)^(+/-) mice with tamoxifen to rescue PU.1 function,the allergic asthmatic inflammation was significantly restored.In vitro studies demonstrate that treatment of PU.1-deficient macrophages with IL-4 attenuated the expression of chitinase 3-like 3(Ym-1)and resistin-like molecule alpha 1(Fizz-1),two specific markers of AAM polarization.In addition,PU.1 expression in macrophages was inducible in response to IL-4 challenge,whichwas associated with phosphorylation of signal transducer and activator of transcription 6(STAT6).Furthermore,DRAchallenge in sensitized mice almost abrogated gene expression of Ym-1 and Fizz-1 in lung tissues of PU/ER(T)^(+/-) mice compared with WT mice.These data,all together,indicate that PU.1 plays a critical role in AAM polarization and asthmatic inflammation.

Engagement of TLR and Dectin-1/Syk Signaling Is Required for Activation of Notch Targets in Dendritic Cells

Pattern-recognition receptors,such as toll-like receptors(TLRs),detect a wide range of microbial products and initiate innate immune responses leading to the production of inflammatory mediators.In addition,TLR signaling also activates expression of Notch target genes that play crucial roles in suppression of TLR-triggered inflammatory responses.However,whether TLR signaling pathways engaged by other classes of pattern-recognition receptors induce expression of Notch target genes remains unclear.Here we demonstrate that zymosan,a stimulus for TLR2 and dectin-1,strongly induces expression of multiple Notch target genes in both human and murine dendritic cells.Mechanistically,induction of Notch targets by zymosan is both TLR2-and Syk-dependent through activation of mitogen-activated protein kinases and the transcription factor c-Fos.Hence,our data reveals a novel mechanism that efficient induction of Notch target genes requires engagement of TLR and dectin-1/Syk signaling pathways.