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 investiga...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.展开更多
基金supported by NIH R01 HL075557,HL068610,and T32 HL082547 and the Department of Veterans Affairs Merit Review Grant 5I01BX000108supported by the grant from National Natural Science Foundation of China(81373424)the Specialized Research Fund for the Doctoral Program of Higher Education of China(20130073120108).
文摘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.
