SUMMARY Macrophages reside in essentially all tissues of the body and play key roles in innate and adaptive immune responses. Distinct populations of tissue macrophages also acquire context-specific functions that are important for normal tissue homeostasis. To investigate mechanisms responsible for tissue-specific functions, we analyzed the transcriptomes and enhancer landscapes of brain microglia and resident macrophages of the peritoneal cavity. In addition, we exploited natural genetic variation as a genome-wide ‘mutagenesis’ strategy to identify DNA recognition motifs for transcription factors that promote common or subset-specific binding of the macrophage lineage-determining factor PU.1. We find that distinct tissue environments drive divergent programs of gene expression by differentially activating a common enhancer repertoire and by inducing the expression of divergent secondary transcription factors that collaborate with PU.1 to establish tissue–specific enhancers. These findings provide insights into molecular mechanisms by which tissue environment influences macrophage phenotypes that are likely to be broadly applicable to other cell types.

ImportanceAcne vulgaris is an inflammatory disease of the pilosebaceous unit of the skin that primarily involves the face and trunk and affects approximately 9% of the population worldwide (approximately 85% of individuals aged 12-24 years, and approximately 50% of patients aged 20-29 years). Acne vulgaris can cause permanent physical scarring, negatively affect quality of life and self-image, and has been associated with increased rates of anxiety, depression, and suicidal ideation.ObservationsAcne vulgaris is classified based on patient age, lesion morphology (comedonal, inflammatory, mixed, nodulocystic), distribution (location on face, trunk, or both), and severity (extent, presence or absence of scarring, postinflammatory erythema, or hyperpigmentation). Although most acne does not require specific medical evaluation, medical workup is sometimes warranted. Topical therapies such as retinoids (eg, tretinoin, adapalene), benzoyl peroxide, azelaic acid, and/or combinations of topical agents are first-line treatments. When prescribed as a single therapy in a randomized trial of 207 patients, treatment with tretinoin 0.025% gel reduced acne lesion counts at 12 weeks by 63% compared with baseline. Combinations of topical agents with systemic agents (oral antibiotics such as doxycycline and minocycline, hormonal therapies such as combination oral contraception [COC] or spironolactone, or isotretinoin) are recommended for more severe disease. In a meta-analysis of 32 randomized clinical trials, COC was associated with reductions in inflammatory lesions by 62%, placebo was associated with a 26% reduction, and oral antibiotics were associated with a 58% reduction at 6-month follow-up. Isotretinoin is approved by the US Food and Drug Administration for treating severe recalcitrant nodular acne but is often used to treat resistant or persistent moderate to severe acne, as well as acne that produces scarring or significant psychosocial distress.Conclusions and RelevanceAcne vulgaris affects approximately 9% of the population worldwide and approximately 85% of those aged 12 to 24 years. First-line therapies are topical retinoids, benzoyl peroxide, azelaic acid, or combinations of topicals. For more severe disease, oral antibiotics such as doxycycline or minocycline, hormonal therapies such as combination oral conceptive agents or spironolactone, or isotretinoin are most effective.

Most guidelines on neonatal skin care emphasize issues pertaining to healthy, term infants. Few address the complex task of skin barrier maintenance in preterm, very preterm, and extremely preterm infants. Here, we provide an evidence‐based review of the literature on skin care of preterm neonates. Interestingly, the stratum corneum does not fully develop until late in the third trimester, and as such, the barrier function of preterm skin is significantly compromised. Numerous interventions are available to augment the weak skin barrier of neonates. Plastic wraps reduce the incidence of hypothermia while semipermeable and transparent adhesive dressings improve skin quality and decrease the incidence of electrolyte abnormalities. Tub bathing causes less body temperature variability than sponge bathing and can be performed as infrequently as once every four days without increasing bacterial colonization of the skin. Topical emollients, particularly sunflower seed oil, appear to reduce the incidence of skin infections in premature neonates—but only in developing countries. In developed countries, studies indicate that topical petrolatum ointment increases the risk of candidemia and coagulase‐negative Staphylococcus infection in the preterm population, perhaps by creating a milieu similar to occlusive dressings. For preterm infants with catheters, povidone‐iodine and chlorhexidine are comparably effective at preventing catheter colonization. Further studies are necessary to examine the safety and efficacy of various skin care interventions in premature infants with an emphasis placed on subclassifying the patient population. In the interim, it may be beneficial to develop guidelines based on the current body of evidence.

Although macrophages can be polarized to distinct phenotypes in vitro with individual ligands, in vivo they encounter multiple signals that control their varied functions in homeostasis, immunity, and disease. Here, we identify roles of Rev-erb nuclear receptors in regulating responses of mouse macrophages to complex tissue damage signals and wound repair. Rather than reinforcing a specific program of macrophage polarization, Rev-erbs repress subsets of genes that are activated by TLR ligands, IL4, TGFβ, and damage-associated molecular patterns (DAMPS). Unexpectedly, a complex damage signal promotes co-localization of NF-κB, Smad3, and Nrf2 at Rev-erb-sensitive enhancers and drives expression of genes characteristic of multiple polarization states in the same cells. Rev-erb-sensitive enhancers thereby integrate multiple damage-activated signaling pathways to promote a wound repair phenotype.DOI: http://dx.doi.org/10.7554/eLife.13024.001