Alternative macrophage activation and lung host defense against Pneumocystis murina (111.20)

Abstract

Abstract We have recently reported that Src TKO mice, which demonstrate augmented lung clearance of P. murina (PM) (Infect Immun, May 2009), have enhanced expression of alternative macrophage activation (M2a) markers such as RELM-α and Arg-1 as well as the M2a-associated chemokines CCL17 and CCL22 (J Immunol, February 2011). We have subsequently discovered that M2a development is a specific response to PM lung infection as AMs isolated from PM-infected mice have increased expression of RELM-α and Arg-1 and produce CCL17 and CCL22 ex vivo. Moreover, M2a development during PM lung infection requires CD4 T cells, as their depletion leads to an inability to maintain optimal lung expression of M2a markers. A putative effector function of the M2a response is CCL17/CCL22-mediated recruitment of eosinophils. Analysis of eosinophil peroxidase mRNA expression revealed increased levels in Src TKO mice and decreased levels in CD4-depleted mice, which directly correlated to the magnitude of M2a development in these two models. In preliminary studies, mice deficient in eosinophils demonstrated impaired PM lung clearance. In addition, administration of simvastatin to mice increased AM M2a marker expression and reduced PM lung burden. Collectively, our data provides evidence that M2a development is the natural immune response to PM, a response regulated by SFKs and requires CD4 T cells for maintenance. Moreover, our work supports a role for eosinophils in lung host defense against Pneumocystis.