Autocrine IL-10 induces hallmarks of alternative activation in macrophages and suppresses antituberculosis effector mechanisms without compromising T cell immunity.
Elevated IL-10 has been implicated in reactivation tuberculosis (TB). Since macrophages rather than T cells were reported to be the major source of IL-10 in TB, we analyzed the consequences of a macrophage-specific overexpression of IL-10 in transgenic mice (macIL-10-transgenic) after aerosol infection with Mycobacterium tuberculosis (Mtb). MacIL-10 transgenic mice were more susceptible to chronic Mtb infection than nontransgenic littermates, exhibiting higher bacterial loads in the lung after 12 wk of infection and dying significantly earlier than controls. The differentiation, recruitment, and activation of Th1 cells as well as the induction of IFN-gamma-dependent effector genes against Mtb were not affected by macrophage-derived IL-10. However, microarray analysis of pulmonary gene expression revealed patterns characteristic of alternative macrophage activation that were overrepresented in Mtb-infected macIL-10 transgenic mice. Importantly, arginase-1 gene expression and activity were strikingly enhanced in transgenic mice accompanied by a reduced production of reactive nitrogen intermediates. Moreover, IL-10-dependent arginase-1 induction diminished antimycobacterial effector mechanisms in macrophages. Taken together, macrophage-derived IL-10 triggers aspects of alternative macrophage activation and promotes Mtb recrudescence independent of overt effects on anti-TB T cell immunity.
Schreiber
Tanja
T
Infection Immunology Research, Research Center Borstel, Borstel, Germany.
Ehlers
Stefan
S
Heitmann
Lisa
L
Rausch
Alexandra
A
Mages
Jörg
J
Murray
Peter J
PJ
Lang
Roland
R
Hölscher
Christoph
C
D000818:Animals; D001119:Arginase / Q000235:genetics; D019898:Autocrine Communication / Q000276:immunology*; D020869:Gene Expression Profiling; D016753:Interleukin-10 / Q000502:physiology*; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis; D013601:T-Lymphocytes / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology*
D016753:Interleukin-10; D001119:Arginase