Autocrine IL-10 Induces Hallmarks of Alternative Activation in Macrophages and Suppresses Antituberculosis Effector Mechanisms without Compromising T Cell Immunity

Abstract

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-γ-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.

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

“…This is in line with the antagonistic effect of IL-10 on microbicidal activities of Mtb-infected macrophages, such as phagosome-lysosome fusion [63,64], and IFNγ-induced production of oxygen and nitrogen species [65]. Likewise, mice overexpressing IL-10 specifically in the macrophage compartment present susceptibility to Mtb infection due to macrophages displaying an exaggerated M2-like activation program associated with a high pulmonary bacterial load [66]. In parallel, we also demonstrate that CD16 + CD163 + MerTK + pSTAT3 + monocyte-macrophages display an immunomodulatory functional capacity.…”

Induction of M2-like macrophages in recipient NOD-scid mice by allogeneic donor CD4+CD25+ regulatory T cells

“…Furthermore, the enhanced phagocytosis and decreased antigenpresenting ability of the host resident macrophages that were induced by the allogeneic donor CD4 1 CD25 1 Tregs could be rescued by the arginase inhibitor, BEC, in vivo. [7][8][9]11,30,43,44 These data provide metabolic enzyme evidence for the presence of polarized recipient M2-like macrophages and further suggest that the induction of M2-like macrophages by donor allogeneic CD4 1 CD25 1 Tregs is significantly dependent on arginase signaling pathways.…”

“…5,6 Th1 cells can drive classical M1 polarization of macrophages via interferon (IFN)-c. These M1 cells are characterized by their ability to release large amounts of pro-inflammatory cytokines, such as IL-12, IL-23 and tumor necrosis factor (TNF), reactive nitrogen intermediates and reactive oxygen intermediates, increased expression of MHC II and costimulatory molecules, efficient antigen presentation and microbicidal or tumoricidal activity. 7,8 Through the expression of cytokines and chemokines, such as IL-12, CXCL9 and CXCL10, M1 macrophages drive the polarization and recruitment of Th1 cells, thereby amplifying a type 1 response. 9 The Th2 cell-derived cytokines, IL-4 and IL-13, direct M2 polarization of macrophages during helminth infection and allergy.…”

Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas

“…Murine studies argue that Arg1 participates in dampening effective immunity against Mtb, because aerosol Mtb-infected mice that are deficient in macrophage-specific Arg1 have lower bacterial loads and smaller cellular infiltrates in the lungs than similarly infected WT mice (22). Moreover, Mtb aerosol infection of transgenic mice that overexpress IL-10 and IL-13 in macrophages results in increased pulmonary expression of Arg1, correlating with increased bacterial loads as compared with WT mice (25,26). In these mouse models, Arg1 expression was linked to reduced production of RNIs, suggesting that L-arginine depletion by Arg1 suppresses NOS2 activity and, therefore, Mtb killing (22,25).…”