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Macrophages and innate immune memory against Staphylococcus infections COMMENTARY Jonas D. Van Belleghema and Paul L. Bollykya,1

There is a growing appreciation that macrophages Emerging evidence suggests that innate immune contribute to innate immune memory against micro- cells, including , macrophages, and natural bial in ways that are distinct from and killer cells, might also be capable of developing complementary to adaptive immune memory. In immunological memory of previous encounters, a trait PNAS, Chan et al. (1) report that macrophages de- previously associated with the adaptive system alone. velop memory against Staphylococcus aureus skin These cell types can undergo a profound phenotypic and skin structure infections (SSSIs) and that this mem- reprogramming upon exposure to microbial stimuli ory is tissue specific and can be transferred between that influences their response to secondary infections individual animals. (12). Innate immune cells respond to microbial expo- Immune memory against S. aureus is important be- sures by increasing the expression of relevant pattern- cause of the immense impact of this microbe on hu- recognition receptors [-associated molecu- man health and because effective against lar patterns (PAMPs)], thereby increasing their affinity recurrent S. aureus infections can be difficult to for particular pathogens. Called “” achieve. S. aureus is the most common cause of skin (13), this model could conceivably include a diverse infections (2). These are often associated with massive set of epigenetic mechanisms. For example, Yoshida morbidity, mortality, and health care expenditures (3). et al. (14) demonstrated that the stress response tran- Patients often experience high rates of recurrence (4), scription factor ATF7 mediates LPS-induced epigenetic suggesting that some individuals have difficulty with changes in macrophages that lead to enhanced pro- establishing protective immunity against this organ- tection against pathogens. ism. in particular can often be in- Along with PAMPs and the response to infection, effective because directed against S. innate memory may also be relevant to damage- aureus virulence factors may not be sufficient for pro- associated molecular patterns (DAMPs) and tissue tection (5). Consistent with this, individuals with im- damage. Weavers et al. (15) demonstrated that apo- paired humoral immunity are not necessarily at ptotic corpse engulfment by Drosophila macrophages increased risk for S. aureus infections (6), and an effec- triggers calcium-induced JNK signaling and the up- tive vaccine against S. aureus has thus far proved elu- regulation of the damage receptor Draper, thus pro- sive (7). Memory responses, while robust, can viding a molecular memory that allows the cell to rap- likewise be ineffectual (8). These data suggest that idly respond to subsequent injury or infection. adaptive immunity alone is unlikely to provide effec- Macrophages are perhaps particularly well suited tive protection against S. aureus infection. for roles in innate memory, given their rapid appear- Studies of individuals with recurrent S. aureus in- ance at sites of infection, their ability to sample the fections in the context of a primary inflammatory environment, and their remarkable phe- have revealed critical roles for select cell types and notypic plasticity (16). By changing levels of PAMP and immune mechanisms in protection against this potential DAMP receptors on their surface, macrophages may pathogen. These include defects in IL-17 production as- adapt and reshape their phenotype in complex and sociated with hyper-IgE syndrome (Job’s disease) (9). context-specific ways. IL-17 was likewise shown in mouse models of S. aureus In PNAS, Chan et al. (1) explore the role of infection to be critical for recruitment, ab- macrophage-mediated innate memory against S. au- scess formation, and bacterial clearance (10). However, reus skin infections. This study builds on their previous − − the mechanisms by which Th17-polarized responses are work in -deficient rag1 / mice demon- mounted in the absence of effective adaptive immunity strating that infection results in a protective innate against S. aureus have been unclear (11). memory response. They additionally observed that

aDivision of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305 Author contributions: J.D.V.B. and P.L.B. wrote the paper. The authors declare no conflict of interest. Published under the PNAS license. See companion article on page E11111. 1To whom correspondence should be addressed. Email: [email protected]. Published online November 2, 2018.

www.pnas.org/cgi/doi/10.1073/pnas.1816935115 PNAS | November 20, 2018 | vol. 115 | no. 47 | 11865–11867 Downloaded by guest on September 29, 2021 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 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, inducible by IFN-γ; RANTES, regulated upon activation, normal T cell expressed and secreted; SA, S. aureus.

this protection was localized to the skin and that the effectors transfer into naive skin afforded protective efficacy in vivo, reduc- + involved included macrophages and dendritic cells ing skin lesion severity and MRSA burden in the skin. (17). In the current study, they analyze the efficacy and mecha- These findings are notable for several reasons. First, the finding nisms of this protective immunity in recurrent methicillin- that macrophages can acquire memory during S. aureus infection resistant S. aureus (MRSA) infection in wild-type mice, focusing and confer protective immunity to naive recipient hosts upon trans- on signatures and cellular effectors of immune memory. fer demonstrates that innate immune memory is cell intrinsic and They assess four key aspects of protective immunity to MRSA not predicated on the immediate tissue environment. This raises during recurrent SSSI in a mouse model: (i) time-dependent the possibility that autologous innate immune memory could be protection, (ii) cytokine signatures of protective immunity in skin manipulated in a controlled manner ex vivo and then transferred to vs. invasive infection, (iii) cellular correlates of protective immu- promote the resolution of wound infections, for example. nity in these tissue contexts, and (iv) the impact of priming Second, they find that this innate memory in macrophages can on the in vivo transferability of immune memory by primed also polarize other neighboring cells in ways that drive antibac- macrophages. terial, Th17, and M1 responses, as well as bacterial clearance. This Chan et al. (1) report that the generation of innate immune suggests that not only do macrophages retain memory of pre- memory from naive macrophages involves several priming events vious exposures but they also shape the responses of other cells. (Fig. 1). Priming resulted in early induction of IL-6 by day 2, fol- Third, they find that these effects are local and specific to the lowed by induction of IL-17A by day 7, which correlated with an affected tissue. This suggests that innate immune memory may be increased Th17 cell presence. Priming also resulted in increased site specific. Again, this may have relevance for the development populations in abscesses and enhanced levels of of therapies targeting innate immune memory. monokine inducible by IFN-γ (MIG); regulated upon activation, Together, Chan et al.’s (1) data support the hypothesis that normal T cell expressed and secreted (RANTES); and IFN-γ– immune memory is integral to protection against recurrent MRSA induced protein 10 (IP-10) in the —ostensibly promoting infections in the skin. These findings greatly enhance our under- T cell recruitment to abscesses. No changes in T cell populations standing of innate immune memory against S. aureus in the skin. were observed in the draining , suggesting that the However, several areas remain to be addressed in future expansion of Th17 cells occurred proximate to sites of infection. studies. For example, the mechanisms underlying macrophage The priming of potentiated S. aureus-specific phagocytic killing innate memory in this model are unclear. Are particular PAMPs or by -derived macrophages in vitro and their adoptive DAMPs involved in this response? The molecular basis of the

11866 | www.pnas.org/cgi/doi/10.1073/pnas.1816935115 Van Belleghem and Bollyky Downloaded by guest on September 29, 2021 tissue and ligand restriction seen in this study is also undefined. Is S. aureus and other microbes have ways to subvert innate immune the tissue-specific nature of macrophage immune memory due to memory that would be important to understand. diminished trafficking or site-directed migration? Lastly, this work and other manuscripts, including some re- More broadly, it would be important to establish that innate viewed here, raise the exciting possibility that it may be possible immune memory against S. aureus is present in humans. Mice to harness macrophage innate immunity to promote clearance raised in sterile conditions are immunologically naive and their of S. aureus skin infections. These are exciting areas for future skin and fur flora is vastly different from that in humans. It would discovery. also be important to understand the plasticity of these pheno- “ ” types. Once a macrophage is programmed to respond to S. Acknowledgments aureus, can it be reprogrammed? Does memory programming This work was supported, in part, by National Institutes of Health Grants R01 affect the longevity of a macrophage? One might also expect that AI12492093 and R21AI133370 and a grant from the Falk Medical Trust (to P.L.B.).

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Van Belleghem and Bollyky PNAS | November 20, 2018 | vol. 115 | no. 47 | 11867 Downloaded by guest on September 29, 2021