Faculty Bibliography

At birth, microbes rapidly colonize our epithelial surfaces. In this issue of Cell Host & Microbe, Leech et al. (2019) uncover how the neonatal immune system discriminates between a colonizing commensal and pathogen to selectively generate tolerance to commensal species.

Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5'-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPARα) reduced monocyte mobilization from the bone marrow. Importantly, we show that fasting improves chronic inflammatory diseases without compromising monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.

Cancer development requires a favorable tissue microenvironment. By deleting MyD88 in keratinocytes or specific bone marrow subpopulations in oncogenic RAS mediated skin carcinogenesis, we show that IL-17 from infiltrating T cells and IkBz signaling in keratinocytes are essential to produce a permissive microenvironment and tumor formation. Both normal and RAS transformed keratinocytes respond to tumor promoters by activating canonical NF-kB and IkBz signaling, releasing specific cytokines and chemokines that attract Th17 cells through MyD88 dependent signaling in T cells. The release of IL-17 into the microenvironment elevates IkBz in normal and RAS transformed keratinocytes. Activation of IkBz signaling is required for the expression of specific promoting factors induced by IL-17 in normal keratinocytes and constitutively expressed in RAS-initiated keratinocytes. Deletion of IkBz in keratinocytes impairs RAS mediated benign tumor formation. Transcriptional profiling and gene set enrichment analysis of IkBz-deficient RAS-initiated keratinocytes indicate that IkBz signaling is common for RAS transformation of multiple epithelial cancers. Probing TCGA data sets using this transcriptional profile indicates that reduction of IkBz signaling during cancer progression associates with poor prognosis in RAS-driven human cancers. Implications: The paradox that elevation of IkBz and stimulation of IkBz signaling through tumor extrinsic factors is required for RAS mediated benign tumor formation while relative IkBz expression is reduced in advanced cancers with poor prognosis implies that tumor cells switch from microenvironmental dependency early in carcinogenesis to cell autonomous pathways during cancer progression.

The skin epithelium covers our body and serves as a vital interface with the external environment. Here, we review the context-specific interactions between immune cells and the epithelium that underlie barrier fitness and function. We highlight the mechanisms by which these two systems engage each other and how immune-epithelial interactions are tuned by microbial and inflammatory stimuli. Epithelial homeostasis relies on a delicate balance of immune surveillance and tolerance, breakdown of which results in disease. In addition to their canonical immune functions, resident and recruited immune cells also supply the epithelium with instructive signals to promote repair. Decoding the dialogue between immunity and the epithelium therefore has great potential for boosting barrier function or mitigating inflammatory epithelial diseases.

The skin interfaces with the external environment and is home to a myriad of immune cells that patrol the barrier to ward off harmful agents and aid in tissue repair. The formation of the cutaneous immune arsenal begins before birth and evolves throughout our lifetime, incorporating exogenous cues from microbes and inflammatory encounters, to achieve optimal fitness and function. Here, we discuss the context-specific signals that drive productive immune responses in the skin epithelium, highlighting key modulators of these reactions, including hair follicles, neurons, and commensal microbes. We thus also discuss the causal and mechanistic underpinning of inflammatory skin diseases that have been revealed in recent years. Finally, we discuss the non-canonical functions of cutaneous immune cells including their burgeoning role in epithelial regeneration and repair. The rapidly growing field of cutaneous immunity is revealing immune mechanisms and functions that can be harnessed to boost skin health and treat disease.

As an interface with the environment, the skin is a complex ecosystem colonized by many microorganisms that coexist in an established balance. The cutaneous microbiome inhibits colonization with pathogens, such as Staphylococcus aureus, and is a crucial component for function of the epidermal barrier. Moreover, crosstalk between commensals and the immune system is now recognized because microorganisms can modulate both innate and adaptive immune responses. Host-commensal interactions also have an effect on the developing immune system in infants and, subsequently, the occurrence of diseases, such as asthma and atopic dermatitis (AD). Later in life, the cutaneous microbiome contributes to the development and course of skin disease. Accordingly, in patients with AD, a decrease in microbiome diversity correlates with disease severity and increased colonization with pathogenic bacteria, such as S aureus. Early clinical studies suggest that topical application of commensal organisms (eg, Staphylococcus hominis or Roseomonas mucosa) reduces AD severity, which supports an important role for commensals in decreasing S aureus colonization in patients with AD. Advancing knowledge of the cutaneous microbiome and its function in modulating the course of skin disorders, such as AD, might result in novel therapeutic strategies.

Adult stem cells are responsible for life-long tissue maintenance. They reside in and interact with specialized tissue microenvironments (niches). Using murine hair follicle as a model, we show that when junctional perturbations in the niche disrupt barrier function, adjacent stem cells dramatically change their transcriptome independent of bacterial invasion and become capable of directly signaling to and recruiting immune cells. Additionally, these stem cells elevate cell cycle transcripts which reduce their quiescence threshold, enabling them to selectively proliferate within this microenvironment of immune distress cues. However, rather than mobilizing to fuel new tissue regeneration, these ectopically proliferative stem cells remain within their niche to contain the breach. Together, our findings expose a potential communication relay system that operates from the niche to the stem cells to the immune system and back. The repurposing of proliferation by these stem cells patch the breached barrier, stoke the immune response and restore niche integrity.

Stem cells regenerate tissues in homeostasis and under stress. By taking cues from their microenvironment or "niche," they smoothly transition between these states. Immune cells have surfaced as prominent members of stem cell niches across the body. Here, we draw parallels between different stem cell niches to explore the context-specific interactions that stem cells have with tissue-resident and recruited immune cells. We also highlight stem cells' innate ability to sense and respond to stress and the enduring memory that forms from such encounters. This fascinating crosstalk holds great promise for novel therapies in inflammatory diseases and regenerative medicine.