Innate Immunity: Physical barriers

Skin surface

Environment that is high in saline, nutrition deficient, acidic, cool, and dry making it hostile to microbial growth

Internal environment

Nutrition (carbon and nitrogen-rich), neutral pH, warm, and moist making it favorable for microbial growth

Constant presence

barrier defenses that function continuously without prior exposure

Non‑specificity

barrier defenses that act broadly against many pathogen types

Multi‑layered protection

combined mechanical, (keratinocytes (skin) mucus layer and cell junction(intestine)) chemical (sweat and oil production/AMPs), and microbiological (normal flora) defenses of physical barrier layers

Epidermis

the outermost skin layer forming the frontline physical barrier

Keratinocytes

>90% of epidermal cells that form the physical barrier and produce cytokines, signaling messenger proteins

Stratum corneum

outer keratinized layer providing strong mechanical protection

IL‑1 family cytokines

keratinocyte‑derived inflammatory cytokines activated by proteases

Sebaceous glands

holocrine glands producing sebum with antimicrobial properties

Hair follicle keratinocytes

cells producing chemokines such as CCL2 and CCL20 during inflammation

Normal flora

commensal microbes that compete with pathogens and induce host AMPs; primes the immune system to maintain response production

Antimicrobial peptides (AMPs)

small cationic peptides that kill microbes and modulate immunity

Cathelicidin

the first mammalian skin AMP, activated into LL‑37 by protease cleavage; breakdown bacterial membrane leading to leakage that eventually eliminates it

LL‑37

active cathelicidin peptide that disrupts microbial membranes and acts as an alarmin

Defensins

small cationic AMPs with direct killing and immune‑modulatory functions; acts as a effector and signal protein

Innate immune cells

dendritic epidermal T cell, dendritic cell, (ILC2) type 2 innate lymphoid cell, (LHC) Langerhans cell, monocyte-derived DC, macrophage, and Natural Killer T cell are all found in the human skin; resident and recruited cells providing rapid, non‑specific defense

Langerhans cell (LC)

epidermal sentinel mediating both immune activation and tolerance

Innate lymphoid cells (ILCs)

tissue‑resident innate cells divided into ILC1, ILC2, ILC3, NK, and LTi subsets

ILC1

type‑1 immunity cells producing IFN‑γ against intracellular pathogens; found in peripheral blood

ILC2

type‑2 immunity cells producing IL‑5 and IL‑13 and promoting wound healing; found in tissues

ILC3

type‑3 immunity cells producing IL‑17 and IL‑22 against extracellular bacteria and fungi; found in tissues

Wound‑induced IL‑33

epithelial alarmin that activates ILC2s during tissue repair

ILC depletion

loss of ILCs leading to delayed wound healing

Intestinal mucus layer

mechanical barrier in the intestine preventing microbial contact with epithelium

Paneth cells

small‑intestinal cells producing AMPs such as Reg3γ to maintain intestinal homeostasis

Balanced mucosal immunity

coordinated AMP production, mucus secretion, and immune signaling maintaining homeostasis

Dysbiosis

imbalance of gut microbiota contributing to mucosal barrier dysfunction

IBD initiation

early breakdown of mucosal barriers leading to inflammation progression