Allergic signaling
IL-4/IL-13 receptor signaling↓
Also searched as IL-4/IL-13 receptor signaling.
This is the other inflammatory arm. IL-17 drives psoriasis; IL-4/IL-13 drives eczema and allergic airway disease. Treating one does not treat the other, which is why both appear here.
In depth
IL-4 and IL-13 signaling through the shared receptor — the branch of immunity behind allergic and atopic disease.
What drives it
Innate immune sensor increases it.
The innate receptor sets the Th2 tone: TLR4 signaling on pulmonary epithelial cells induces a Th2-polarising response through Th2-inducing dendritic cells, and the airway epithelium drives allergic disease by producing pro-Th2 cytokines including IL-4 and IL-13 (PMC3189122). An UNMAPPED negative feedback runs the other way: IL-13 dampens airway-epithelial innate immunity by inducing IRAK-M, and IL-4/IL-13 downregulate TLR4 expression in human epithelium (JACI S0091-6749(11)01740-4; J Immunol 176:5805). PMC3189122
The Long Tenant increases it.
Cestode antigens polarise the mucosal response toward Th2 with IL-4 and IL-13 production. PMID 17187651
Roundworm burden increases it.
Nematode infection elicits the canonical IL-4/IL-13 type-2 expulsion response in the gut. doi 10.1038/s41598-024-65281-0
Fluke burden increases it.
The schistosome egg granuloma is an IL-13-dependent type-2 inflammatory lesion. doi 10.1371/journal.pone.0135360
Parasite burden increases it.
Parasite burden polarises the host toward a type-2 response with IL-4 and IL-13. doi 10.3389/fimmu.2018.02293
What it drives
It increases Calm skin barrier.
Atopic dermatitis is an IL-4/IL-13 disease, shown interventionally: dupilumab is a monoclonal antibody against the shared alpha subunit of the IL-4 receptor, blocking both IL-4 and IL-13 signaling, FDA-approved for moderate-to-severe atopic dermatitis and sustaining improvement in signs, symptoms and quality of life for up to five years (PMC11954541). Blocking one receptor pair controls the disease. The route is JAK/STAT-mediated repression of barrier genes FLG, LOR, IVL, CLDN1 and AQP3, giving impaired keratinocyte differentiation, tight-junction disruption and increased permeability -- now drawn explicitly as the JAK → Atopic Dermatitis link. filaggrin null mutation is itself associated with barrier dysfunction and raised AD risk independent of cytokine signaling, and IL-17E (IL-25) suppresses filaggrin synthesis in keratinocytes -- so the barrier defect has genetic and non-Th2 contributors this arrow does not carry. Th22 and Th17 responses also contribute to chronic AD lesions, especially in pediatric, intrinsic and Asian patients. PMC11954541
It increases Clears blocked nose & sinuses.
Chronic rhinosinusitis with nasal polyps is a predominantly type 2 inflammatory disease of the nasal cavity and paranasal sinuses, and the same receptor that drives eczema drives it: dupilumab binds IL-4Rα, the shared receptor component for IL-4 and IL-13. In the phase 3 SINUS-24 and SINUS-52 trials (724 patients, on background intranasal corticosteroids) it reduced polyp size, sinus opacification and symptom severity against placebo — nasal congestion improved 57% and 51% versus 19% and 15% on placebo — and it is now an approved indication (PMC9081188, PMC11161870). Note: this is the polyp-forming, type-2 form of sinus disease. An infectious or structural blocked sinus is a different problem and this pathway does not describe it. PMC9081188
It reduces Innate immune sensor.
IL-13 dampens airway epithelial innate immunity by inducing IRAK-M, a negative regulator of TLR signaling (J Allergy Clin Immunol S0091-6749(11)01740-4), and IL-4/IL-13 downregulate TLR4 expression and function in human intestinal epithelial cells (J Immunol 2006;176:5805-5814). This closes a negative-feedback loop: TLR4 drives Th2 cytokines including IL-13, and IL-13 in turn restrains TLR4. Human epithelial cells. Verified at source before addition -- gates 2 and 3 cleared.
It reduces Bone health.
Named across six reviews of bone remodeling and osteoarthritis pathogenesis. Bone remodeling relies on the coordinated actions of bone-resorbing osteoclasts, bone-forming osteoblasts, and osteocytes serving as mechanosensors and local remodeling coordinators. PMC10648156
It increases Eases allergy load.
This is the same axis as eczema, and it splits the same way: type 2 endotypes are IL-4/IL-5/IL-13-driven and eosinophilic, while non-type-2 endotypes ARE driven by increased Th1 and Th17 responses, resulting in elevated neutrophil levels. Two endotypes, two cell types, two nodes. And the intervention evidence is unusually direct: dupilumab (IL-4Ralpha inhibitor) reduces polyp burden and restores smell, while MEPOLIZUMAB (anti-IL-5) and OMALIZUMAB (anti-IgE) address specific endotypes - three biologics, three targets, three endotype-matched responses. PMC11059040
It reduces Gut barrier.
10.3389/fphar.2023.1301800 — The aging outcome lists the thirteen hallmarks themselves, each mapped to its pathway and labeled with its hallmark number. (from the reviews of this outcome). Verbatim: “IL-13 causes increased permeability and delayed repair of model colon epithelial cell monolayers by stimulating apoptosis and increasing expression of the pore-forming tight junction protein claudin-2”. doi 10.3389/fphar.2023.1301800 · PMC3120916
It reduces Skin.
10.3389/fmed.2023.1165098 — The aging outcome lists the thirteen hallmarks themselves, each mapped to its pathway and labeled with its hallmark number. (from the reviews of this outcome). Verbatim: “IL-4 and IL-13 do inhibit the expression of IVL, LOR, FLG, and FLG2 in keratinocytes in vitro”. doi 10.3389/fmed.2023.1165098 · PMC7432778
It reduces Supports airflow & lung function.
10.1172/JCI5909 — Drawn from reviews of neighboring outcomes rather than from studies of this outcome itself, which is weaker evidence, and the map marks it so. Verbatim: “IL-13, a critical cytokine in asthma, causes emphysema with enhanced lung volumes and compliance, mucus metaplasia, and inflammation, when inducibly overexpressed in the adult murine lung”. doi 10.1172/JCI5909 · PMID 11067861 · PMC301418
It increases The Door The Fat Comes In Through.
Type 2 inflammation raises FATP2 in the airway lining. Verbatim: 'Inhibition of IL-4/IL-13 signaling by dupilumab reduces expression of lipid peroxidation-associated genes, including SLC27A2' (Exp Mol Med 2025, doi 10.1038/s12276-025-01440-1, PMID 40195539). human nasal epithelium; not tested in liver or fat. doi 10.1038/s12276-025-01440-1 · PMID 40195539
Blends that modulate it
Each blend page names this pathway and carries the study behind its claim.
See it on the map
Open the causal map to follow this pathway upstream and downstream, arrow by arrow, each with its study.