Advances in molecular pathogenesis of hidradenitis suppurativa: Dysregulated keratins and ECM signaling
Open accessAbstract
Hidradenitis suppurativa (HS) is characterized by deep-seated, highly inflamed, and painful lumps/abscesses, fistulae, and sinus tracts that grow extensively deep in the dermis and are highly immunogenic in nature. Evidence for the role of γ-secretase mutations along with dysregulated Notch signaling in HS is strong in about one-third of the HS patients, however, the role of dysregulated Notch signaling in HS pathogenesis in relation to hair follicle alterations and hyper-activation of the immune system remains undefined. GWAS, proteomic data and functional investigations of identified sequence variants in HS pathology are not fully revealing. The disease initiation or progression may involve bacterial infection besides defects in the intrinsic functions of keratinocytes, which may be key to further exacerbate the immune infiltration and cytokine production in and around the lesional tissue. The unavailability of a suitable animal model that could fully recapitulate the pathogenesis of HS is a major impediment in the complete understanding of the underlying mechanisms and development of effective treatments. Dysregulation in keratinocytes, dermal fibroblasts and the presence of extracellular matrix (ECM) degradation products that ultimately affect immune regulation are key components of HS pathogenesis. Bacterial infection further exacerbates the complexity of the disease progression. While anti-TNFα therapy shows partial efficacy, no effective treatment is available to cure HS. Multiple clinical trials targeting various cytokines, complement C5a and ECM products are in progress. This review provides updated information on some of these aspects with a focus on dysregulated keratinocyte and immune cells and role of ECM, and Keratin functions in this regard.
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Diagnostic histopathological features of inflammatory dermatoses reflect disease-specific immune mechanisms that increasingly inform therapeutic targeting.
“These features are not only diagnostically useful but also reflect disease-specific immune mechanisms that increasingly inform therapeutic targeting across inflammatory dermatoses [1,2,3,4,5].”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
The Introduction (page not provided) links histological inflammation in hidradenitis suppurativa (HS) to cytokine activity and describes responses to targeted treatments. It does not establish that histopathological features are diagnostically useful across inflammatory dermatoses; it says exact diagnosis of HS remains difficult without better mechanistic understanding. (LLM, conf=0.85)
Experimental — accuracy not yet measuredT lymphocytes play a central role in coordinating disease-specific immune responses, with distinct subtypes such as Th1, Th2, and Th17 driving various inflammatory phenotypes.
“T lymphocytes play a central role in coordinating disease-specific immune responses, with distinct subtypes such as T helper 1 (Th1), T helper 2 (Th2), and T helper 17 (Th17) driving various inflammatory phenotypes.”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
The “Plasma cells, B cells and T cells” section reports increased Th17 infiltration and pro-inflammatory cytokines in hidradenitis suppurativa skin. The paper thus supports a role for Th17 in inflammation, but our copy does not establish the claimed roles of Th1 and Th2 or describe distinct inflammatory phenotypes driven by all three subtypes. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMorphological findings in atopic dermatitis reflect the underlying Th2-skewed cytokine milieu, particularly IL-4 and IL-13 signaling, which contributes to impaired epidermal differentiation, barrier dysfunction, and persistent local immune activation.
“These morphological findings reflect the underlying Th2-skewed cytokine milieu, particularly IL-4 and IL-13 signaling, which contributes to impaired epidermal differentiation, barrier dysfunction, and persistent local immune activation [3,5].”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThe cutaneous immune microenvironment consists of a highly coordinated network of cells, including keratinocytes, dendritic cells, macrophages, and T lymphocytes.
“The cutaneous immune microenvironment consists of a highly coordinated network of cells, including keratinocytes, dendritic cells, macrophages, and T lymphocytes.”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
Keratinocytes act as immune modulators, producing cytokines and chemokines that influence immune cell recruitment and activation.
“Keratinocytes act as immune modulators, producing cytokines and chemokines that influence immune cell recruitment and activation, reinforcing the concept of the skin as an active immune organ rather than merely a passive barrier [1,5].”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
Spongiosis is the most consistent finding in acute atopic dermatitis lesions and is observed in most biopsies.
“Spongiosis represents the most consistent finding in acute lesions and is observed in most biopsies”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
The Introduction (page unavailable) describes early hidradenitis suppurativa lesions in terms of follicular hyperkeratosis and inflammation, not spongiosis. Searches for “spongiosis” and “atopic dermatitis spongiosis” found no passage in our copy addressing whether spongiosis is the most consistent finding in acute atopic dermatitis lesions or occurs in most biopsies. (LLM, conf=0.76)
Experimental — accuracy not yet measuredTissue-resident memory T cells contribute to the persistence and recurrence of inflammation.
“In addition to circulating immune cells, tissue-resident memory T cells contribute to the persistence and recurrence of inflammation, emphasizing the importance of local immune regulation.”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
The ‘Plasma cells, B cells and T cells’ section describes T-cell infiltration in HS skin but does not identify tissue-resident memory T cells or link them to persistent or recurrent inflammation. The ‘Macrophages and DCs’ section discusses recurrence in connection with occult inflammation and plasmacytoid dendritic cells. Searches for ‘tissue-resident memory T cells,’ ‘resident memory,’ and ‘memory T cells’ found no passage supporting the attributed role; page numbers were unavailable. (LLM, conf=0.72)
Experimental — accuracy not yet measuredEosinophils are variably present in atopic dermatitis and depend on disease stage and severity.
“whereas eosinophils are variably present and depend on disease stage and severity.”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
The Keratins and HS section mentions atopic dermatitis only in relation to altered keratin expression. Searches for eosinophils and for variation by disease stage or severity found no passage addressing the attributed claim; the immune-cell passages instead discuss hidradenitis suppurativa. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIn the dermis of atopic dermatitis, a superficial perivascular inflammatory infiltrate composed mainly of lymphocytes is typically observed.
“In the dermis, a superficial perivascular inflammatory infiltrate composed mainly of lymphocytes is typically observed.”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
The Introduction describes lymphocytic inflammation around hair follicles in hidradenitis suppurativa, not a superficial perivascular infiltrate in atopic dermatitis. Searches for atopic dermatitis and perivascular lymphocytic infiltration found no passage in our copy addressing the claimed finding. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe presence of eosinophils supports a type 2 inflammatory background in clinically compatible atopic dermatitis lesions.
“Their presence supports a type 2 inflammatory background, particularly in clinically compatible lesions.”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
The Keratins and HS section mentions atopic dermatitis only in connection with altered keratin expression. The Neutrophils section discusses immune infiltration in hidradenitis suppurativa, but our copy does not address whether eosinophils indicate type 2 inflammation in atopic dermatitis lesions (searched: eosinophils, atopic dermatitis, type 2 inflammation). (LLM, conf=0.78)
Experimental — accuracy not yet measuredAdditional histopathological findings in atopic dermatitis may include papillary dermal edema in acute lesions and dermal fibrosis or lichenification-related changes in chronic disease.
“Additional findings may include papillary dermal edema in acute lesions and dermal fibrosis or lichenification-related changes in chronic disease [4,5].”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
The ECM and HS section discusses collagen deposition and fibrosis in hidradenitis suppurativa, not atopic dermatitis. Searches for atopic dermatitis, papillary dermal edema, and lichenification found no passage addressing the claimed acute or chronic findings; no page numbers were available in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measuredEosinophils may be present in atopic dermatitis, but their number is variable and they are not required for diagnosis.
“Eosinophils may be present, although their number is variable and they are not required for diagnosis.”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
The 'Dysregulated immune system and HS' passages discuss immune cells in hidradenitis suppurativa, not eosinophils in atopic dermatitis. Searches for eosinophils, variability in their number, and diagnostic requirements found no passage addressing the claim; absence of a passage is not a contradiction. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe combination of spongiosis, superficial perivascular lymphocytic inflammation, variable eosinophils, and chronic epidermal remodeling is highly suggestive of atopic dermatitis in the appropriate clinical context.
“From a diagnostic perspective, the combination of spongiosis, superficial perivascular lymphocytic inflammation, variable eosinophils, and chronic epidermal remodeling is highly suggestive of atopic dermatitis in the appropriate clinical context.”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
The Introduction describes follicular inflammation and psoriasiform hyperplasia in hidradenitis suppurativa, not diagnostic findings of atopic dermatitis. Searches for spongiosis, perivascular lymphocytic inflammation, eosinophils, and atopic dermatitis found no passage in our copy addressing the claimed combination. (LLM, conf=0.76)
Experimental — accuracy not yet measuredMorphological and molecular features of atopic dermatitis directly underpin the development of targeted drugs such as dupilumab, tralokinumab, and lebrikizumab.
“These morphological and molecular features directly underpin the development of targeted drugs such as dupilumab, tralokinumab, and lebrikizumab.”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
The Introduction and “Currents Clinical trials” section discuss the pathogenesis and targeted treatments of hidradenitis suppurativa, not atopic dermatitis. Searches for atopic dermatitis and the three named drugs found no passage addressing whether its features underpinned their development. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe characteristic atopic dermatitis features correspond to a type 2 immune response, where cytokines IL-4 and IL-13 activate downstream signaling pathways.
“These features correspond to a type 2 immune response, where cytokines IL-4 and IL-13 activate downstream signaling pathways.”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
The Keratins and HS section mentions atopic dermatitis only as an example of altered keratin expression. The ECM and HS section discusses IL-13 in fibrosis associated with hidradenitis suppurativa, but our copy does not link atopic dermatitis features to a type 2 immune response or describe downstream signaling activated by IL-4 and IL-13 (searched: atopic dermatitis, type 2, IL-4, IL-13, and STAT6). No page numbers were available in the indexed passages. (LLM, conf=0.75)
Experimental — accuracy not yet measuredIn atopic dermatitis, the most characteristic features are spongiosis, epidermal barrier disruption, and a superficial perivascular lymphocytic infiltrate.
“In atopic dermatitis, the most characteristic features are spongiosis, epidermal barrier disruption, and a superficial perivascular lymphocytic infiltrate.”
From The Cutaneous Immune Microenvironment in Selected Inflammatory Skin Diseases: Linking Histopathology, Mechanisms, and Targeted Therapy (2026) · cites this paper as [5]
The Introduction describes follicular hyperkeratosis and perifollicular inflammation in hidradenitis suppurativa, not the characteristic features of atopic dermatitis. The Keratins and HS section mentions atopic dermatitis only in connection with elevated SERPINB3/SERPINB4. Searches for spongiosis and a superficial perivascular lymphocytic infiltrate found no passage addressing the claimed combination of features. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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References 103 · Cited by 22
Research works printed but not linked: 1
- [8]Hurley HJ, Axillary hyperhidrosis, apocrine bromhidrosis, hidradenitis suppurativa and familial benign pemphigus. Surgical approach, Marcel Dekker Inc., New York, 1996, pp. 623– 645.
- Authors
- Kashyap, M. P., Khan, J., Sinha, R., Jin, L., Atigadda, V., Deshane, J. S., Ahmed, A. R., Kilic, A., Raman, C., Mukhtar, M. S., Elmets, C. A., & Athar, M.
- Affiliations
- University of Alabama at Birmingham (US)
- Washington State University Spokane (US)
- Corresponding author
- Athar, Mohammad
- ORCID
- Venue
- Seminars in Cell & Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2022-08
- Volume
- 128
- Pages
- 120-129
- ISSN
- 1084-9521 (ISSN-L)
- PMC
- PMC9232849
- OpenAlex
- W4210327852
- Semantic Scholar
- c37315eceecc005e0834cd218c1fbed6024ea0b6
- Cited by
- 22
- References
- 103
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 6 · 2023: 1 · 2022: 2
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 316 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Seminars in Cell and Developmental Biology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Environmental Health Sciences (RO1 ES026219)
- National Cancer Institute (5P01CA210946)
- 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, keratin, extracellular matrix, Notch signaling, keratinocytes, dermal fibroblasts, bacterial infection, immune cell infiltration, cytokine production, anti-TNF therapy, C5a, animal models, pathogenesis
- MeSH terms
- Animals, Cytoskeletal Proteins, Humans, Keratins, Signal Transduction, Hidradenitis Suppurativa, Proteomics, Genome-Wide Association Study
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