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Open Access Publications from the University of California

Scholarly Works (116 results)

  • Article
  • Peer Reviewed
UC San Diego Previously Published Works (2017)
Human skin contains an abundant and diverse population of microbial organisms. Many of these microbes inhabit follicular structures of the skin. Furthermore, numerous studies have shown that the interaction of some members of the skin microbiome with host cells will result in changes in cell function. However, estimates of the potential for the microbiome to influence human health through skin have ignored the inner follicular surface, and therefore vastly underestimated the potential of the skin microbiome to have a systemic effect on the human body. By calculating the surface area of follicular and the interfollicular epithelial surface it is shown that skin provides a vast interface for interactions with the microbiome.
    Cover page: Human Skin Is the Largest Epithelial Surface for Interaction with Microbes
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2015)
    The mammalian immune system communicates with skin-resident microbes, and some of these microbes provide benefits to the host. In a recent paper in Nature, Naik et al. (2015) provide evidence that the murine epidermis permits S. epidermidis, a skin-specific bacterium, to shape the immune response.
      Cover page: S. epidermidis Influence on Host Immunity: More Than Skin Deep
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2013)
      The skin, the human body's largest organ, is home to a diverse and complex variety of innate and adaptive immune functions. Despite this potent immune system present at the cutaneous barrier, the skin encourages colonization by microorganisms. Characterization these microbial communities has enhanced our knowledge of the ecology of organisms present in normal skin; furthermore, studies have begun to bring to light the intimate relationships shared between host and resident microbes. In particular, it is apparent that just as host immunological factors and behaviors shape the composition of these communities, microbes present on the skin greatly impact the functions of human immunity. Thus, today the skin immune system should be considered a collective mixture of elements from the host and microbes acting in a mutualistic relationship. In this article we will review recent findings of the interactions of skin microbial communities with host immunity, and discuss the role that dysbiosis of these communities plays in diseases of the skin.
        Cover page: Functions of the skin microbiota in health and disease
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2015)
        Cathelicidins are a gene family best known for their antimicrobial action, but the diverse mature peptides they encode also have other host defense functions. The human cathelicidin peptide LL-37 enhances recognition of nucleic acids, an action whose significance is seen in human diseases such as psoriasis where it is associated with increased type 1 IFN production. This function has been attributed to the extracellular action of the peptide to facilitate uptake of nucleic acids. In this study, we demonstrate that the murine mature cathelicidin peptide (CRAMP), encoded by the mouse gene (Camp), is functionally distinct from the human mature peptide (LL-37), as it does not facilitate CpG entry. However, mouse cathelicidin does influence recognition of CpG as bone marrow-derived dendritic cells from Camp(-/-) mice have impaired CpG responses and Camp(-/-) mice had impaired response to CpG given i.v. or s.c. We show that cathelicidin concentrates in Lamp1 positive compartments, is colocalized with CpG in the endolysosome, can be immunoprecipitated with TLR9, and binds to CpG intracellulary. Collectively, these results indicate that the functions of cathelicidin in control of TLR9 activation may include both intracellular and extracellular effects.
          Cover page: Endogenous Intracellular Cathelicidin Enhances TLR9 Activation in Dendritic Cells and Macrophages
          • Thesis
          • Peer Reviewed
          UC San Diego Electronic Theses and Dissertations (2024)

          The aim of this dissertation is to increase the understanding of the complex cellular communication network underlying skin immunity, with a focus on the role of fibroblasts. Dermal fibroblasts are appreciated for supporting tissue architecture and scar formation but have historically been ignored in terms of immunology. I begin this dissertation with a literature review on the topic of fibroblast immune function, which led to my innovative hypothesis that subsets of fibroblasts are critical for skin inflammation and host defense. To test my hypothesis, I performed an unbiased network analysis of mouse skin during Staphylococcus aureus infection and discovered CXCL12+ immune acting fibroblast (IAF) subsets with a dominant role in neutrophil communication. Subsequent experiments to characterize this novel cell population demonstrated that CXCL12+ IAFs predominantly reside in the reticular dermis, express adipocyte lineage markers, detect IL-17 and TNF⍺, and promote robust neutrophil recruitment through NFKBIZ-dependent release of CXCR2 ligands and CXCL12. Targeted deletion of Il17ra in mouse fibroblasts resulted in greatly reduced neutrophil recruitment and increased infection by S. aureus, demonstrating the significance of CXCL12+ IAFs. I next asked if CXCL12+ IAFs are involved in psoriasis, a human inflammatory skin disease responsive to drugs targeting IL-17 and TNF⍺. Using single-cell transcriptomics, analogous CXCL12+ IAFs were identified in human psoriatic skin. Importantly, therapeutic targeting of IL-17 decreased fibroblast expression of neutrophil chemokines, demonstrating that IL-17 inhibitors work, in part, by inhibiting CXCL12+ IAF communication with neutrophils. Finally, to characterize the cell-cell interactions underlying human neutrophilic dermatoses, I performed bulk, single-nuclei, and spatial transcriptomics on skin biopsies from patients with Sweet’s syndrome (SS), pustular psoriasis, and pyoderma gangrenosum. This analysis led to the identification interferon (IFN)-activated IAFs enriched in SS. To test the significance of the IFN signature, I performed experiments with cultured fibroblasts and found that type 1 IFN induced fibroblast expression of neutrophil chemokines, implicating IFN-activated IAFs in SS pathogenesis. In summary, this dissertation unveils the pivotal role of dermal IAFs in orchestrating skin immunity. Using a combination of bioinformatics, in vitro systems, murine models, and clinical samples, this work provides unprecedented insight into the intricate cellular communication network underlying skin inflammation and host defense. These findings contribute significantly to our understanding of immunology and lay the groundwork for the development of novel treatments for infectious and inflammatory diseases.

            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2021)
            This review is intended to illuminate the emerging understanding of epigenetic modifications that regulate both adaptive and innate immunity in the skin. Host defense of the epidermis and dermis involves the interplay of many cell types to enable homeostasis; tolerance to the external environment; and appropriate response to transient microbial, chemical, and physical insults. To understand this process, the study of cutaneous immunology has focused on immune responses that reflect both adaptive learned and genetically programmed innate defense systems. However, recent advances have begun to reveal that epigenetic modifications of chromatin structure also have a major influence on the skin immune system. This deeper understanding of how enzymatic changes in chromatin structure can modify the skin immune system and may explain how environmental exposures during life, and the microbiome, lead to both short-term and long-term changes in cutaneous allergic and other inflammatory processes. Understanding the mechanisms responsible for alterations in gene and chromatin structure within skin immunocytes could provide key insights into the pathogenesis of inflammatory skin diseases that have thus far evaded understanding by dermatologists.
              Cover page: Role of Epigenetics in the Regulation of Immune Functions of the Skin
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2018)
              Acne is one of the most common skin diseases worldwide and results in major health care costs and significant morbidity to severely affected individuals. However, the pathophysiology of this disorder is not well understood. Host-microbiome interactions that affect both innate and adaptive immune homeostasis appear to be a central factor in this disease, with recent observations suggesting that the composition and activities of the microbiota in acne is perturbed. Staphylococcus epidermidis and Cutibacterium acnes (C. acnes; formerly Propionibacterium acnes) are two major inhabitants of the skin that are thought to contribute to the disease but are also known to promote health by inhibiting the growth and invasion of pathogens. Because C. acnes is ubiquitous in sebaceous-rich skin, it is typically labeled as the etiological agent of acne yet it fails to fulfill all of Koch's postulates. The outdated model of acne progression proposes that increased sebum production promotes over-proliferation of C. acnes in a plugged hair follicle, thereby driving inflammation. In contrast, growing evidence indicates that C. acnes is equally abundant in both unaffected and acne-affected follicles. Moreover, recent advances in metagenomic sequencing of the acne microbiome have revealed a diverse population structure distinct from healthy individuals, uncovering new lineage-specific virulence determinants. In this article, we review recent developments in the interactions of skin microbes with host immunity, discussing the contribution of dysbiosis to the immunobiology of acne and newly emerging skin microbiome-based therapeutics to treat acne.
                Cover page: Host-microbiome interactions and recent progress into understanding the biology of acne vulgarisCreative Commons 'BY' version 4.0 license
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2013)
                An abundant and diverse collection of bacteria, fungi, and viruses inhabits the human skin. These microorganisms vary between individuals and between different sites on the skin. The factors responsible for the unique variability of the skin microbiome are only partly understood, but results suggest that host genetic and environmental influences play a major role. Today, the steady accumulation of data describing the skin microbiome, combined with experiments designed to test the biological functions of surface microbes, has provided new insights into links between human physiology and skin microbiota. This review describes some of the current information regarding the skin microbiome and its impact on human health. Specifically, we summarize the present understanding of the function of microbe-host interactions on the skin and highlight some unique features that distinguish skin commensal organisms from pathogenic microbes.
                  Cover page: Structure and function of the human skin microbiome
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2017)
                  Patients with atopic dermatitis are frequently colonized by Staphylococcus aureus. If S. aureus is present, then the subject tends to have more severe disease. However, it is unclear if S. aureus is a cause of atopic dermatitis or a consequence of the abnormal epithelial environment. In this issue of the Journal of Investigative Dermatology, Meylan et al. present evidence from a prospective clinical trial that shows that S. aureus colonization precedes onset of atopic dermatitis in children. These observations suggest that S. aureus may cause atopic dermatitis in some individuals.
                    Cover page: Evidence that Human Skin Microbiome Dysbiosis Promotes Atopic Dermatitis
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2014)
                    UV radiation poses a significant risk to human health. The mechanisms that help repair UV-damaged cells have recently been more clearly defined with the observation that Toll-like receptor 3 can sense self RNA released from necrotic keratinocytes following UV damage. TLR3 activation in the skin induces inflammation and increases the expression of genes involved in skin barrier repair. Activation of TLR2 in the skin by commensal microbial products prevents excessive inflammation by blocking downstream TLR3 signaling. This review highlights how UV damage-induced inflammation in the skin is propagated by host products and regulated by host inhabitants.
                      Cover page: UVB Radiation Illuminates the Role of TLR3 in the Epidermis
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