IRAK4 Is Overexpressed in Hidradenitis Suppurativa Skin and Correlates with Inflammatory Biomarkers
Open accessAbstract
Hidradenitis suppurativa (HS) is a chronic inflammatory disease manifesting as painful dermal nodules, abscesses, and tunnels. Activation of the IL-1R/toll-like receptor pathway is strongly implicated in the pathogenesis of HS; thus, the role of a key signaling node, IRAK4, was investigated in a noninterventional study (NCT04440410) that enrolled 30 patients with HS. IRAK4 expression was evaluated in blood and lesional, perilesional, and nonlesional skin biopsies. PBMCs expressed IRAK4, with significantly higher levels in monocytes (P ≤ .0001). Ex vivo treatment of PBMCs with KT-474, a targeted degrader of IRAK4, robustly decreased IRAK4 in all immune cell types from healthy volunteers and patients with HS. Ex vivo treatment of toll-like receptor-stimulated healthy donor monocytes with KT-474 decreased IRAK4 protein levels and inhibited inflammatory cytokine production. In HS skin samples, IRAK4 protein levels were significantly higher in lesional than in nonlesional tissue (P ≤ .0001), and IRAK4-positive immune infiltrate increased with greater disease severity. Multiple inflammatory mediators were upregulated in HS lesional skin, correlating with IRAK4 overexpression. These data confirm the significance of the IL-1R/toll-like receptor pathway in the pathogenesis of HS and provide support for ongoing clinical studies evaluating KT-474 in the treatment of HS.
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Neutrophils contribute to tissue injury in hidradenitis suppurativa through proteases, reactive oxygen species, and neutrophilic extracellular traps.
“Neutrophils contribute to tissue injury through proteases, reactive oxygen species, and neutrophilic extracellular traps (NETs).”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [41]
Epithelium-lined tunnels in hidradenitis suppurativa act as immunologically active niches, maintaining chronic inflammation and impairing resolution.
“The resulting epithelium-lined tunnels act as immunologically active niches, maintaining chronic inflammation and impairing resolution [40,41].”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [41]
Hidradenitis suppurativa represents a reprogrammed cutaneous microenvironment in which epithelial dysfunction, immune dysregulation, microbial persistence, and stromal remodeling are tightly integrated.
“Thus, hidradenitis represents a reprogrammed cutaneous microenvironment in which epithelial dysfunction, immune dysregulation, microbial persistence, and stromal remodeling are tightly integrated [40,41,42].”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [41]
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“The resulting epithelium-lined tunnels act as immunologically active niches, maintaining chronic inflammation and impairing resolution [40,41].”
- Authors
- McDonald, A., Karnik, R., Campbell, V., Davis, J., Chavoshi, S., Slavin, A., Sharma, K., Gollob, J., & Alavi, A.
- Affiliations
- GlaxoSmithKline (Canada) (CA)
- Corresponding author
- McDonald, Alice
- ORCID
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2025-02
- Volume
- 145
- Issue
- 2
- Pages
- 323-333.e10
- ISSN
- 0022-202X (ISSN-L)
- OpenAlex
- W4401068832
- Cited by
- 11
- References
- 27
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 2
- FWCI
- 4.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Dermatology › Hidradenitis Suppurativa and Treatments
- Health Sciences › Medicine › Epidemiology › Autoimmune and Inflammatory Disorders
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- hidradenitis suppurativa, IRAK4, monocytes, lesional skin, inflammatory cytokines, immune cell infiltration, disease severity, chronic inflammatory skin disease
- MeSH terms
- Adult, Biopsy, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Severity of Illness Index, Skin, Biomarkers, Case-Control Studies, Hidradenitis Suppurativa, Inflammation Mediators, Interleukin-1 Receptor-Associated Kinases, Young Adult
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