Aberrant Th2 inflammation drives dysfunction of alveolar macrophages and susceptibility to bacterial pneumonia

The ubiquitin ligase,Itch,is required to prevent autoinflammatory disease in mice and humans.Itch-deficient mice develop lethal pulmonary inflammation characterized by the production of Th2 cytokines(for example,interleukin-4(IL-4));however,the contribution of Itch to immune defense against respiratory pathogens has not been determined.We found that Itch-deficient mice were highly susceptible to intranasal infection with the respiratory pathogen Klebsiella pneumoniae.Infected Itch-deficient mice exhibited increased immune cell infiltration,cytokine levels and bacterial burden in the respiratory tract compared with control mice.However,numbers of resident alveolar macrophages were reduced in the lungs from Itch-deficient mice both before and after infection.High levels of Th2 cytokines in the respiratory tract correlated with deceased alveolar macrophages,and genetic ablation of IL-4 restored alveolar macrophages and host defense to K.pneumoniae in Itch-deficient mice,suggesting that loss of alveolar macrophages occurred as a consequence of Th2 inflammation.Adoptive transfer of Itch−/−CD4+T cells into Rag−/−mice was sufficient to drive reduction in numbers of Itch-replete alveolar macrophages.Finally,we found that Stat6 signaling downstream of the IL-4 receptor directly reduced fitness of alveolar macrophages when these cells were exposed to the Itch−/−inflamed respiratory tract.These data suggest that Th2 inflammation directly impairs alveolar macrophage fitness in Itch−/−mice,and elucidate a previously unappreciated link between Th2 cells,alveolar macrophages and susceptibility to bacterial infection.