Src-family tyrosine kinases regulate alveolar macrophage alternative activation during Pneumocystis murina lung infection (37.28)

Abstract

Abstract We have previously shown that mice triple-deficient in the Src-family tyrosine kinases (SFKs) Hck, Fgr and Lyn (SrcTKO mice) have augmented innate lung clearance of P.murina as a result of elevated proinflammatory cytokine (e.g. IL-1β) and chemokine (e.g. CCL2/MCP-1) levels and increased inflammatory cell recruitment. Augmented clearance in SrcTKO mice correlates with a higher ability of alveolar macrophages (AMs) from these mice to kill P.murina in vitro, though this enhancement is not associated with elevated AM inflammatory responses. Since SrcTKO AMs are not hyper-inflammatory yet kill more efficiently, we hypothesized that they have a different activation pattern compared to WT. We show that AMs and whole lungs from P.murina-infected SrcTKO mice express higher mRNA and protein levels of the alternative macrophage activation markers RELM-α and Arg-1 compared to WT. There is surprisingly no difference in the levels of the pro-alternative activation cytokines IL-4 and IL-13 or other cytokines known to modulate AM activation, e.g. IFN-γ or GM-CSF. However, infected SrcTKO mice have higher lung levels of M-CSF, CCL17/TARC and the IL-4/IL-13 receptor, IL4ra. Treatment of WT AMs with IL-4 or IL-13 enhances their ability to kill P.murina, while a blockade of IL4ra or inhibition of phagolysosome maturation inhibits killing. These results indicate that SFKs regulate AM activation during P.murina infection, and that alternatively activated AMs are better equipped to kill P.murina.