Macrophages are mononuclear phagocytes that act as tissue-immune sentinels and perform critical homeostatic functions, including phagocytosing spent cells, recycling nutrients, remodeling tissues, and resolving inflammation 1, 2. Armed with arsenals of cell surface and cytosolic pattern recognition receptors (PRRs) that sense pathogen-associated molecular patterns (PAMPS), during bacterial infection, macrophages readily phagocytose invading pathogens, release inflammatory mediators to facilitate innate and adaptive immune responses, and kill bacteria via production of reactive metabolites and multistep inflammasome activation 3, 4. Paradoxically, macrophages can also serve as a cellular niche for intracellular bacterial pathogens, such as Salmonella enterica, Bartonella henselae, and Mycobacterium tuberculosis (Mtb), to survive within infected tissues 5, 6, 7. Macrophages exhibit differential polarization, or activation states, and these functional states have distinct cellular phenotypes and functions 8, 9, 10•. Macrophage polarization has been described using a conceptually simplified M1 and M2 framework 11, 12, 13. The classical, or M1, macrophage activation paradigm occurs in microenvironments upon recognition of PAMPs, such as lipopolysaccharides (LPS), and inflammatory immune signaling, such as interferon-γ (IFN-γ). These stimuli activate downstream transcriptional regulators, including nuclear factor-κB (NF-κB) and signal transducer and activator of transcription-1 (STAT1), to generate inflammatory and antibacterial functional states 10•, 11. On the other hand, the alternatively activated, M2- polarized state prototypically entails macrophage activation from the type-2 immunity-associated cytokines such as IL-4 and IL-13 or IL-10 that trigger signal transducer and activator of transcription-6 (STAT6), signal transducer and activator of transcription-3 (STAT3), and peroxisome proliferator-activated receptors (PPARs) among other regulators, to elicit macrophage activities involved in resolving inflammation and tissue repair. The dichotomous M1 and M2 framework does not, however, fully capture the heterogeneous functional states of tissue macrophages in vivo. Increasingly, macrophage polarization and heterogeneous phenotypes have been recognized as a spectrum of functional states, with overlapping cellular features that are shaped by a multitude of factors and dependent on pathophysiological contexts 10•, 14, 15.

Accumulating studies over the past decade have linked macrophage polarization states to differential antibacterial capacity and permissiveness, with an M2-like functional state being more permissive for intracellular bacterial replication and survival 6, 16, 17•, 18. Macrophage ontogeny and microenvironmental factors influence their functional phenotypes, such as antibacterial responses [19]. Intracellular bacteria that exploit macrophages as a cellular niche to establish persistent infection, such as Salmonella enterica serovar Typhimurium (STm), express macromolecular secretion systems to inject virulence effector proteins into the host cell cytoplasm to co-opt cellular activities 5, 20, 21. Thus, in addition to evading antibacterial innate immune responses and exploiting existing favorable macrophage functional states, a fascinating question for some time is whether intracellular bacteria have specific mechanisms to actively skew macrophage polarization toward more permissive, M2-like states. Herein, we review recent research that uncover mechanisms by which Salmonella and other intracellular bacteria employ injected virulence effectors to manipulate macrophage polarization and reprogram macrophage functional states. We highlight how the STAT3 pathway has emerged as a critical cellular target for intracellular bacteria to reprogram macrophages and may represent a convergent bacterial pathogenesis strategy. These fascinating findings from studies of intracellular bacterial infections have broadened our perspectives on macrophage heterogeneity and generate exciting questions for future research that will further our understanding of macrophage immunobiology.