Impairment of alternative macrophage activation delays cutaneous leishmaniasis in nonhealing BALB/c mice

Expressed on various cell types, the IL-4R alpha is a component of both receptors for IL-4 and IL-13. Susceptibility of BALB/c mice to Leishmania major is believed to be dependent on the development of IL-4- and IL-13-producing Th2 cells, while IFN-gamma secretion by Th1 cells is related to resistance. Despite a sustained development of Th2 cells, IL-4R alpha-deficient BALB/c mice are able to control acute cutaneous leishmaniasis, suggesting that IL-4R alpha-bearing cells other than Th2 cells contribute to susceptibility. To analyze the contribution of the IL-4Ra on macrophages, recently generated macrophage/neutrophil-specific IL-4Ra-deficient mice on a susceptible BALB/c genetic background were infected with L. major. Strikingly, macrophage/neutrophil-specific IL-4Ra-deficient mice showed a significantly delayed disease progression with normal Th2 and type 2 Ab responses but improved macrophage leishmanicidal effector functions and reduced arginase activity. Together, these results suggest that alternative macrophage activation contributes to susceptibility in cutaneous leishmaniasis.