During tissue repair, myofibroblasts produce extracellular matrix (ECM) molecules for tissue resilience and strength. Altered ECM deposition can lead to tissue dysfunction and disease. Identification of distinct myofibroblast subsets is necessary to develop treatments for these disorders. Here, using extensive analysis of pro-fibrotic cells during mouse skin wound healing, fibrosis and aging; we identify distinct subpopulations of myofibroblasts, including cells identified as adipocyte precursors (APs). Multiple mouse models and transplantation assays demonstrate that AP proliferation, and not other myofibroblasts, is activated by CD301b-expressing macrophages through IGF1 and PDGFC. With age, wound bed APs and differential gene expression between myofibroblast subsets are reduced. Our findings identify multiple fibrotic cell populations and suggest the environment dictates functional myofibroblast heterogeneity, which is driven by fibroblast-immune interactions after wounding.

Adipocytes undergo pronounced changes in size and behavior to support diverse tissue functions, but the mechanisms that control these changes are not well understood. Mammary gland-associated white adipose tissue (mgWAT) regresses in support of milk fat production during lactation and expands during the subsequent involution of milk-producing epithelial cells, providing one of the most marked physiological examples of adipose growth. We examined cellular mechanisms and functional implications of adipocyte and lipid dynamics in the mouse mammary gland (MG). Using in vivo analysis of adipocyte precursors and genetic tracing of mature adipocytes, we find mature adipocyte hypertrophy to be a primary mechanism of mgWAT expansion during involution. Lipid tracking and lipidomics demonstrate that adipocytes fill with epithelial-derived milk lipid. Furthermore, ablation of mgWAT during involution reveals an essential role for adipocytes in milk trafficking from, and proper restructuring of, the mammary epithelium. This work advances our understanding of MG remodeling and tissue-specific roles for adipocytes.

The skin represents the first line of defense and innate immune protection against pathogens. Skin normally provides a physical barrier to prevent infection by pathogens; however, wounds, microinjuries, and minor barrier impediments can present open avenues for invasion through the skin. Accordingly, wound repair and protection from invading pathogens are essential processes in successful skin barrier regeneration. To repair and protect wounds, skin promotes the development of a specific and complex immunological microenvironment within and surrounding the disrupted tissue. This immune microenvironment includes both innate and adaptive processes, including immune cell recruitment to the wound and secretion of extracellular factors that can act directly to promote wound closure and wound antimicrobial defense. Recent work has shown that this immune microenvironment also varies according to the specific context of the wound: the microbiome, neuroimmune signaling, environmental effects, and age play roles in altering the innate immune response to wounding. This review will focus on the role of these factors in shaping the cutaneous microenvironment and how this ultimately impacts the immune response to wounding.

The skin is an active immune organ that functions as the first and largest site of defense to the outside environment. Serving as the primary interface between host and pathogen, the skin's early immune responses to viral invaders often determine the course and severity of infection. We review the current literature pertaining to the mechanisms of cutaneous viral invasion for classical skin-tropic, oncogenic, and vector-borne skin viruses. We discuss the skin's evolved mechanisms for innate immune viral defense against these invading pathogens, as well as unique strategies utilized by the viruses to escape immune detection. We additionally explore the roles that demographic and environmental factors, such as age, biological sex, and the cutaneous microbiome, play in altering the host immune response to viral threats.

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Antiviral proteins (AVPs) including the oligoadenylate-synthase (OAS) and Interferon induced transmembrane protein (IFITM) families have protective roles within the innate immune system. However, little is known about their regulation in skin. BMAL1 and CLOCK, regulators of the circadian rhythm, have known importance in a number of immune functions. We hypothesized that the circadian clock may regulate cutaneous AVP expression. We demonstrate that murine skin displays homeostatic oscillations of AVP expression through the day, and that AVPs exhibit modest rhythmic expression in primary human keratinocytes post-circadian synchronization using serum starvation or dexamethasone shock with a periodicity of 20 to 24 hours. siRNA knockdown of CLOCK also decreased AVP expression in vitro. Further in silico analysis revealed that murine and non-human primate skin display circadian expression of AVPs. Notably, we have found that skin wounding at different times of day induces variable AVP expression. Woundinduced transcription of AVPs also was attenuated in ClockD19 circadian mutant mice. These findings support a paradigm where circadian rhythm may control time-of-day anticipatory AVP transcriptional production in order to prioritize cutaneous defenses when the host is more likely to be wounded and encounter pathogens. Further work is needed to establish the mechanistic links of wounding, circadian rhythm, and the AVP response to ultimately permit a better understanding of our skin's homeostatic and wound-induced viral defense mechanisms.

Aged skin is prone to viral infections, but the mechanisms responsible for this immunosenescent immune risk are unclear. We observed that aged murine and human skin expressed reduced antiviral proteins (AVPs) and circadian regulators including Bmal1 and Clock. Bmal1 and Clock were found to control rhythmic AVP expression in skin and such circadian-control of AVPs was diminished by disruption of immune cell interleukin 27 signaling and deletion of Bmal1/Clock genes in mouse skins, as well as siRNA-mediated knockdown of CLOCK in human primary keratinocytes. We found that treatment of circadian enhancing agents, nobiletin and SR8278, reduced infection of herpes simplex virus 1 (HSV1) in epidermal explants and human keratinocytes in a Bmal1/Clock-dependent manner. Circadian enhancing treatment also reversed susceptibility of aging murine skin and human primary keratinocytes to viral infection. These findings reveal an evolutionarily conserved and age-sensitive circadian regulation of cutaneous antiviral immunity, underscoring circadian restoration as an antiviral strategy in aging populations.

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