Choreographing Immunity in the Skin Epithelial Barrier

Abstract

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.

Figure 1:. Mutual crosstalk between epidermal and immune cells during homeostasis and tissue repair.

Hair follicles (HFs) serve as control towers that recruit and position skin-resident immune cells. HFs produce CCL20 to guide Langerhans cells (LCs) entry into epidermis and to position resident-memory T cells (T_RMs), including regulatory T cell (T_regs), and innate lymphoid cells (ILCs). HFs also provide cytokines that T_RMs and ILCs depend on for maintenance. Integrins αvβ6 and αvβ8 expressed on keratinocytes activate TGF-β that is required for epidermal retention of LCs and T_RMs. Immune cells also send vital signals to orchestrate homeostatic maintenance of hair cycle and sebaceous glands and direct tissue-repair. T_regs express the Notch ligand, Jagged 1 (JAG1), and promote hair regeneration. TNF-producing macrophages, which are recruited by HF-derived CCL2, activate the hair regeneration program. In the natural cycle, resident macrophages produce stem cell activating Wnts to induce hair cycling. ILCs regulate sebaceous gland function to tune skin microbial equilibrium. FGF9 produced by dermal γδ T cells amplifies WNT signaling to promote wound-induced hair neogenesis. Epithelialization in wounds is mediated by immune cell-derived factors including epidermal growth factor receptor (EGFR) ligands and fibroblast growth factors (FGFs).

Figure 2:. Perturbations to keratinocytes trigger and harness immune responses.

Keratinocytes sense microorganisms and other environmental stressors through Toll-like receptors (TLRs), Rig-like receptors (RLRs), NOD-like receptors (NLRs) and AIM2-inflammasomes and transmit the signals to immune cells. Upon infection by intracellular pathogens such as bacteria and viruses, keratinocytes produce IL-1β and TNF to initiate type 1 and type 17 immune responses, which further leads to the recruitment of neutrophils and activation of macrophages. Extracellular parasites, toxins and tissue damage promote type 2 immune responses via epithelial cell-derived alarmins TSLP, IL-33 and IL-25. The immunological pathways that are poised against infectious agents, when dysregulated, play central roles in inflammatory skin diseases such as psoriasis and atopic dermatitis.

Figure 3:. Dialogue between the microbiota and immune cells in skin.

Resident Commensal bacteria are required for tuning type 17 responses and promoting wound healing in the skin., Commensal derived the short-chain fatty acid (SCFA) and lipoteichoic acid (LTA) modulate immunity. T_regs generated against commensal bacteria early in life enable symbiosis with the host. The immune cells bolster the epidermal barrier by by enhancing the production of antimicrobial peptides and lipids to limit bacterial penetration and community dysbiosis. This effect is regulated by immune derived -type 17 cytokines and ILC-mediated regulation of sebum. The dialogue between the host and microbiota is discordant in inflammatory skin diseases such as atopic dermatitis, wherein dysbiosis, predominated by Staphylococcus aureus, drives atopic skin inflammation.