Type I IFN Induces IL-10 Production in an IL-27–Independent Manner and Blocks Responsiveness to IFN-γ for Production of IL-12 and Bacterial Killing in Mycobacterium tuberculosis–Infected Macrophages

Abstract

Tuberculosis, caused by the intracellular bacterium Mycobacterium tuberculosis, currently causes ∼1.4 million deaths per year, and it therefore remains a leading global health problem. The immune response during tuberculosis remains incompletely understood, particularly regarding immune factors that are harmful rather than protective to the host. Overproduction of the type I IFN family of cytokines is associated with exacerbated tuberculosis in both mouse models and in humans, although the mechanisms by which type I IFN promotes disease are not well understood. We have investigated the effect of type I IFN on M. tuberculosis–infected macrophages and found that production of host-protective cytokines such as TNF-α, IL-12, and IL-1β is inhibited by exogenous type I IFN, whereas production of immunosuppressive IL-10 is promoted in an IL-27–independent manner. Furthermore, much of the ability of type I IFN to inhibit cytokine production was mediated by IL-10. Additionally, type I IFN compromised macrophage activation by the lymphoid immune response through severely disrupting responsiveness to IFN-γ, including M. tuberculosis killing. These findings describe important mechanisms by which type I IFN inhibits the immune response during tuberculosis.

Mycobacterium tuberculosis Differentially Activates cGAS- and Inflammasome-Dependent Intracellular Immune Responses through ESX-1

“…This finding agrees with the literature, where a correlation between IFN-b production and the virulence of W-Beijing strains has been established (Manca et al, 2001;. Moreover, a recent investigation of the association between type I IFN production and bacterial virulence demonstrated a role for type I IFN in inducing the immunosuppressive cytokine IL-10 and in repressing the cytoprotective effect of IFN-g in Mtb-infected macrophages (McNab et al, 2014). These results are consistent with our data, which show both strongly suppressed production of IL-10 and enhanced macrophage survival in cGAS knockout and STING knockout cells.…”

Keap1 regulates inflammatory signaling in Mycobacterium avium -infected human macrophages

“…S5B). Results could thus not be ascribed to auto-and paracrine activity of individual cytokines despite the well-characterized importance of these cytokines in mycobacterial defenses (2,3,7,18,39,40). We therefore propose that Keap1 acts as a negative regulator for controlling inflammatory signaling in M. avium-infected human primary macrophages.…”

C-type lectin receptor DCIR modulates immunity to tuberculosis by sustaining type I interferon signaling in dendritic cells

“…S9E). Type I IFNs are known to inhibit IL-12-p70 in myeloid cells, including DCs (27), and in particular in M. tuberculosis-infected monocytes and macrophages (28,29). Accordingly, stimulation by IFNβ resulted in a strong suppression of IL-12-p70 production by TLR2-activated In I, cells were left untreated or were treated with the SHP2 inhibitor GS-493 (24).…”