Dupilumab and tralokinumab each reduced IGFL4 expression in lesional atopic dermatitis (AD) skin, investigators at Indiana University School of Medicine report in a study published online September 30, 2026 in The Journal of Investigative Dermatology.

The work, led by Matthew J. Turner, MD, PhD, with first authors Qun Wang, PhD, Gloria R. Xue, MS, and Hong-Ming Zhou, PhD, frames IGFL1 and IGFL4 as IL-4/IL-13–responsive amplifiers of allergic skin inflammation. The authors propose a positive feedback loop between type 2 cytokines and IGFLs, sustained by keratinocyte-derived IGFL production.

What does the transcriptomic analysis show?

The team reanalyzed the public AD dataset GSE121212 (Tsoi et al., 2019). They identified 342 differentially expressed genes (log2 fold change >2, adjusted p < 0.05) between healthy control skin and lesional AD skin — 229 upregulated and 113 downregulated in lesions. Both IGFL1 and IGFL4 rose significantly, and IGFL4 localized to the epidermis.

How does the IL-4/IL-13–IGFL axis operate?

To test causality, the group used the oxazolone (Oxa) Th2-driven murine model of allergic skin inflammation. Mice were sensitized with 2.0% Oxa on day 1 and challenged with 1.0% Oxa on day 6; ear thickness was measured 24 hours post-challenge. In Oxa-treated skin, Igfl induction followed Il4 expression.

Knockout experiments clarified the consequences of removing IGFL signaling:

• Igfl-deficient mice showed significant reductions in disease severity markers
• RNA sequencing and qPCR revealed lower Il4, Il13, and other type 2 inflammation-associated transcripts
• Loss of Igfl blunted IL-4Rα–dependent induction in vivo

In vitro, IL-4 and IL-13 each drove Igfl transcription in murine keratinocytes; IFNγ did not. The same stimuli induced IGFL4 in human keratinocytes, supporting cross-species conservation. The authors conclude: "These data suggest there is a positive feedback loop between IL-4/IL-13 and IGFLs that can promote allergic skin inflammation."

What is the clinical signal?

The investigators next asked whether approved IL-4Rα–targeting biologics interrupt the loop. AD patients receiving dupilumab or tralokinumab showed decreased IGFL4 expression in lesional skin. The reduction parallels the type 2 cytokine blockade that defines both drugs' mechanism and positions IGFL4 as a candidate pharmacodynamic biomarker of IL-4/IL-13 pathway activity.

Where does the research go next?

IGFL1 had previously been linked to AD (Zhou et al., 2023), but its regulatory logic was undefined. The current study extends that finding by identifying IGFL4 as a parallel IL-4/IL-13–responsive transcript and naming keratinocytes as the cellular source. Igfl-deficient mice exhibited dampened type 2 inflammation in the Oxa model, suggesting IGFLs operate in tight reciprocity with the cytokine cascade.

Future work will test whether neutralizing antibodies or small-molecule inhibitors against IGFLs blunt allergic dermatitis severity in preclinical models. Tralokinumab's transcriptomic footprint in AD, published separately in JID in 2025 by Tandon et al., already supports a dynamic IL-13–driven response that the new work now ties to keratinocyte IGFL output.

The authors declared no conflicts of interest. Bulk RNA sequencing data generated for the study are deposited under GEO accession GSE305766.