There is a growing appreciation that macrophages contribute to innate immune memory against microbial pathogens in ways that are distinct from and complementary to adaptive immune memory. In PNAS, Chan et al. (1) report that macrophages develop memory against Staphylococcus aureus skin and skin structure infections (SSSIs) and that this memory is tissue specific and can be transferred between individual animals.

Immune memory against S. aureus is important because of the immense impact of this microbe on human health and because effective immunity against recurrent S. aureus infections can be difficult to achieve. S. aureus is the most common cause of skin infections (2). These are often associated with massive morbidity, mortality, and health care expenditures (3). Patients often experience high rates of recurrence (4), suggesting that some individuals have difficulty with establishing protective immunity against this organism. Humoral immunity in particular can often be ineffective because antibodies directed against S. aureus virulence factors may not be sufficient for protection (5). Consistent with this, individuals with impaired humoral immunity are not necessarily at increased risk for S. aureus infections (6), and an effective vaccine against S. aureus has thus far proved elusive (7). Memory T cell responses, while robust, can likewise be ineffectual (8). These data suggest that adaptive immunity alone is unlikely to provide effective protection against S. aureus infection.

Studies of individuals with recurrent S. aureus infections in the context of a primary immunodeficiency have revealed critical roles for select cell types and immune mechanisms in protection against this potential pathogen. These include defects in IL-17 production associated with hyper-IgE syndrome (Job’s disease) (9). IL-17 was likewise shown in mouse models of S. aureus infection to be critical for neutrophil recruitment, abscess formation, and bacterial clearance (10). However, the mechanisms by which Th17-polarized responses are mounted in the absence of effective adaptive immunity against S. aureus have been unclear (11).

Emerging evidence suggests that innate immune cells, including monocytes, macrophages, and natural killer cells, might also be capable of developing immunological memory of previous encounters, a trait previously associated with the adaptive system alone. These cell types can undergo a profound phenotypic reprogramming upon exposure to microbial stimuli that influences their response to secondary infections (12). Innate immune cells respond to microbial exposures by increasing the expression of relevant pattern-recognition receptors [pathogen-associated molecular patterns (PAMPs)], thereby increasing their affinity for particular pathogens. Called “trained immunity” (13), this model could conceivably include a diverse set of epigenetic mechanisms. For example, Yoshida et al. (14) demonstrated that the stress response transcription factor ATF7 mediates LPS-induced epigenetic changes in macrophages that lead to enhanced protection against pathogens.

Along with PAMPs and the response to infection, innate memory may also be relevant to damage-associated molecular patterns (DAMPs) and tissue damage. Weavers et al. (15) demonstrated that apoptotic corpse engulfment by Drosophila macrophages triggers calcium-induced JNK signaling and the up-regulation of the damage receptor Draper, thus providing a molecular memory that allows the cell to rapidly respond to subsequent injury or infection.

Macrophages are perhaps particularly well suited for roles in innate memory, given their rapid appearance at sites of infection, their ability to sample the inflammatory environment, and their remarkable phenotypic plasticity (16). By changing levels of PAMP and DAMP receptors on their surface, macrophages may adapt and reshape their phenotype in complex and context-specific ways.

In PNAS, Chan et al. (1) explore the role of macrophage-mediated innate memory against S. aureus skin infections. This study builds on their previous work in lymphocyte-deficient rag1^−/− mice demonstrating that infection results in a protective innate memory response. They additionally observed that this protection was localized to the skin and that the effectors involved included macrophages and Langerin⁺ dendritic cells (17). In the current study, they analyze the efficacy and mechanisms of this protective immunity in recurrent methicillin-resistant S. aureus (MRSA) infection in wild-type mice, focusing on cytokine signatures and cellular effectors of immune memory. They assess four key aspects of protective immunity to MRSA during recurrent SSSI in a mouse model: (i) time-dependent protection, (ii) cytokine signatures of protective immunity in skin vs. invasive infection, (iii) cellular correlates of protective immunity in these tissue contexts, and (iv) the impact of priming on the in vivo transferability of immune memory by primed macrophages.

Chan et al. (1) report that the generation of innate immune memory from naive macrophages involves several priming events (Fig. 1). Priming resulted in early induction of IL-6 by day 2, followed by induction of IL-17A by day 7, which correlated with an increased Th17 cell presence. Priming also resulted in increased dendritic cell populations in abscesses and enhanced levels of monokine inducible by IFN-γ (MIG); regulated upon activation, normal T cell expressed and secreted (RANTES); and IFN-γ–induced protein 10 (IP-10) in the blood—ostensibly promoting T cell recruitment to abscesses. No changes in T cell populations were observed in the draining lymph node, suggesting that the expansion of Th17 cells occurred proximate to sites of infection. The priming of potentiated S. aureus-specific phagocytic killing by bone marrow-derived macrophages in vitro and their adoptive transfer into naive skin afforded protective efficacy in vivo, reducing skin lesion severity and MRSA burden in the skin.

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Fig. 1.

The generation of innate immune memory from naive macrophages involves several priming events. In PNAS, Chan et al. report that exposure of macrophages to S. aureus results in early induction of IL-6 by day 2, followed by induction of IL-17A by day 7. This leads to enhanced MIG, RANTES, and IP-10 levels and the polarization of local immunity toward Th17 and M1 responses. The priming of potentiated S. aureus-specific phagocytic killing by bone marrow-derived macrophages in vitro and their adoptive transfer into naive skin afforded protective efficacy in vivo, reducing skin lesion severity and MRSA burden in the skin. IP-10, IFN-γ–inducible protein 10; MIG, monokine inducible by IFN-γ; RANTES, regulated upon activation, normal T cell expressed and secreted; SA, S. aureus.

These findings are notable for several reasons. First, the finding that macrophages can acquire memory during S. aureus infection and confer protective immunity to naive recipient hosts upon transfer demonstrates that innate immune memory is cell intrinsic and not predicated on the immediate tissue environment. This raises the possibility that autologous innate immune memory could be manipulated in a controlled manner ex vivo and then transferred to promote the resolution of wound infections, for example.

Second, they find that this innate memory in macrophages can also polarize other neighboring cells in ways that drive antibacterial, Th17, and M1 responses, as well as bacterial clearance. This suggests that not only do macrophages retain memory of previous exposures but they also shape the responses of other cells.

Third, they find that these effects are local and specific to the affected tissue. This suggests that innate immune memory may be site specific. Again, this may have relevance for the development of therapies targeting innate immune memory.

Together, Chan et al.’s (1) data support the hypothesis that immune memory is integral to protection against recurrent MRSA infections in the skin. These findings greatly enhance our understanding of innate immune memory against S. aureus in the skin.

However, several areas remain to be addressed in future studies. For example, the mechanisms underlying macrophage innate memory in this model are unclear. Are particular PAMPs or DAMPs involved in this response? The molecular basis of the tissue and ligand restriction seen in this study is also undefined. Is the tissue-specific nature of macrophage immune memory due to diminished trafficking or site-directed migration?

More broadly, it would be important to establish that innate immune memory against S. aureus is present in humans. Mice raised in sterile conditions are immunologically naive and their skin and fur flora is vastly different from that in humans. It would also be important to understand the plasticity of these phenotypes. Once a macrophage is “programmed” to respond to S. aureus, can it be reprogrammed? Does memory programming affect the longevity of a macrophage? One might also expect that S. aureus and other microbes have ways to subvert innate immune memory that would be important to understand.

Lastly, this work and other manuscripts, including some reviewed here, raise the exciting possibility that it may be possible to harness macrophage innate immunity to promote clearance of S. aureus skin infections. These are exciting areas for future discovery.