Turning foes into permissive hosts: manipulation of macrophage polarization by intracellular bacteria

Abstract

Macrophages function as tissue-immune sentinels and mediate key antimicrobial responses against bacterial pathogens. Yet, they can also act as a cellular niche for intracellular bacteria, such as Salmonella enterica, to persist in infected tissues. Macrophages exhibit heterogeneous activation or polarization, states that are linked to differential antibacterial responses and bacteria permissiveness. Remarkably, recent studies demonstrate that Salmonella and other intracellular bacteria inject virulence effectors into the cellular cytoplasm to skew the macrophage polarization state and reprogram these immune cells into a permissive niche. Here, we review mechanisms of macrophage reprogramming by Salmonella and highlight manipulation of macrophage polarization as a shared bacterial pathogenesis strategy. In addition, we discuss how the interplay of bacterial effector mechanisms, microenvironmental signals, and ontogeny may shape macrophage cell states and functions. Finally, we propose ideas of how further research will advance our understanding of macrophage functional diversity and immunobiology.

Figure 1:. Intracellular bacteria manipulate macrophage polarization via STAT3 signaling.

Inside macrophages, S. Typhimurium reside within modified, Salmonella-containing vacuoles and inject the virulence effector SteE through T3SS into cellular cytoplasm. SteE promotes phosphorylation and activation of STAT3 by GSK3. Host IL-6 and IL-10 signaling also induce STAT3 phosphorylation and activation. Phosphorylated STAT3 translocates into the cellular nucleus and regulates expression of target genes, including Il4ra and Arg1, culminating in M2-like, anti-inflammatory responses that are more bacteria permissive, such as enhanced IL-4R/STAT6 signaling and reduced production of Reactive Nitrogen Species (RNS). Similarly, during B. henselae infection, vacuole-residing intracellular bacteria inject the effector BepD through T4SS to mediate phosphorylation of macrophage STAT3 by c-ABL. Whether a macrophage ultimately acting as and antibacterial cell or a permissive niche for bacteria may vary depending on the summative strengths of microenvironmental signals such as of IL-10 and IL-6, other macrophage antimicrobial properties, and the robustness of bacterial effector mechanisms to skew macrophage polarization.