IRF3 inhibits IFN-γ-mediated restriction of intracellular pathogens in macrophages independently of IFNAR

Abstract

Macrophages use an array of innate immune sensors to detect intracellular pathogens and to tailor effective antimicrobial responses. In addition, extrinsic activation with the cytokine IFN-γ is often required as well to tip the scales of the host-pathogen balance toward pathogen restriction. However, little is known about how host-pathogen sensing impacts the antimicrobial IFN-γ-activated state. It was observed that in the absence of IRF3, a key downstream component of pathogen sensing pathways, IFN-γ-primed macrophages more efficiently restricted the intracellular bacterium Legionella pneumophila and the intracellular protozoan parasite Trypanosoma cruzi. This effect did not require IFNAR, the receptor for Type I IFNs known to be induced by IRF3, nor the sensing adaptors MyD88/TRIF, MAVS, or STING. This effect also did not involve differential activation of STAT1, the major signaling protein downstream of both Type 1 and Type 2 IFN receptors. IRF3-deficient macrophages displayed a significantly altered IFN-γinduced gene expression program, with up-regulation of microbial restriction factors such as Nos2. Finally, we found that IFN-γ-primed but not unprimed macrophages largely excluded the activated form of IRF3 from the nucleus following bacterial infection. These data are consistent with a relationship of mutual inhibition between IRF3 and IFN-γ-activated programs, possibly as a component of a partially reversible mechanism for modulating the activity of potent innate immune effectors (such as Nos2) in the context of intracellular infection.

Increased susceptibility to pneumonia due to tumour necrosis factor inhibition and prospective immune system rescue via immunotherapy

“…These findings were synonymous to Kamboj et al.’s study, looking at TNF-α and IFN-γ in M. tuberculosis ( Kamboj et al., 2020 ). The same observation was recently made by Maciag et al., who studied the inhibitory effects of IRF3 on IFN-γ in macrophages, creating a permissive environment to encourage the growth of intracellular pathogens ( Maciag et al., 2021 ). Park & Skerrett had also observed worsening infection in monocytes upon treatment with anti-inflammatory IL-10, even reversing the protective effects of IFN-γ ( Park and Skerrett, 1996 ).…”

Characterization ofNeisseria gonorrhoeaecolonization of macrophages under distinct polarization states and nutrients environment

“…4A). Microbiocidal functions are enhanced in M1 macrophages (48), therefore we investigated whether M1-polarized U937 macrophages under the conditions we used restrict the replication of the vacuolar pathogen Legionella pneumophila as it would be expected (49, 50). Indeed, M1-polarized U937 macrophages significantly restricted Legionella growth as compared to M0 controls (Fig.…”

“…4B-C). Because IFNγ-dependent cell autonomous defenses mainly target intracellular pathogens (50, 51, 52, 53, 54), the lack of growth restriction by M1 macrophages might indicate that either intracellular gonococci can interfere with microbiocidal activities of M1 macrophages or perhaps enhanced replication by surface-associated bacteria compensates for a potential decrease in the intracellular population. To distinguish between those possibilities, we directly measured Ng capacity to invade and grow within M1 macrophages (Figs.…”

Characterization of Neisseria gonorrhoeae colonization of macrophages under distinct polarization states and nutrients environment

“…Successful polarization in the various phenotypic states was confirmed by the upregulation of state-specific cellular markers – IRF1 and IL6 for M1 and IL10 for M2 ( Figure 4A ). Microbiocidal functions are enhanced in M1 macrophages ( Thiriot et al., 2020 ), therefore we investigated whether M1-polarized U937 macrophages under the conditions we used restrict the replication of the vacuolar pathogen Legionella pneumophila as would be expected ( Plumlee et al., 2009 ; Maciag et al., 2022 ). Indeed, M1-polarized U937 macrophages significantly restricted Legionella growth as compared to M0 controls ( Figure 4B ).…”

“…Because IFNγ-dependent cell-autonomous defenses mainly target intracellular pathogens ( Buchmeier and Schreiber, 1985 ; Nacy et al., 1985 ; Suzuki et al., 1988 ; Kak et al., 2018 ; Maciag et al., 2022 ), the lack of growth restriction by M1 macrophages might indicate that either intracellular gonococci can interfere with microbiocidal activities of M1 macrophages or perhaps enhanced replication by surface-associated bacteria compensates for a potential decrease in the intracellular population. To distinguish between those possibilities, we directly measured Ng capacity to invade and grow within M1 macrophages ( Figures 5A–C ).…”