Immunopathogenesis of hidradenitis suppurativa and response to anti–TNF-α therapy

Lowe, Margaret M.; Naik, Haley B.; Clancy, Sean; Pauli, Mariela; Smith, Kathleen M.; Bi, Yingtao; Dunstan, Robert W.; Gudjonsson, Johann E.; Paul, Maia; Harris, Hobart W.; Kim, Esther; Shin, Uk Sok; Ahn, Richard; Liao, Wilson; Hansen, Scott L.; Rosenblum, Michael D.

doi:10.1172/jci.insight.139932

Cited by 97 publications

(127 citation statements)

References 83 publications

(100 reference statements)

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“…Thus, our scRNA-seq data demonstrate similarities between late-stage HS and chronic, non-healing wounds since monocytes/macrophages in both diseases are transcriptionally polarized toward an M1-like phenotype. Our data support previous scRNA-seq performed by Lowe and colleagues, who found decreased abundance of CD163-expressing macrophages in active inflammatory HS lesions ( 50 ). As previously described, CD163 is a characteristic marker of anti-inflammatory M2 macrophages ( 11 ).…”

Section: Discussionsupporting

confidence: 92%

“…As previously described, CD163 is a characteristic marker of anti-inflammatory M2 macrophages ( 11 ). Notably, the authors also observed decreased abundance of CD163-expressing macrophages in non-lesional skin adjacent to HS lesions ( 50 ). Since non-lesional skin may be predisposed to developing HS pathology, further research is needed to clarify the role of macrophages in the transition and pathogenesis from non-lesional skin into lesional skin ( 87 ).…”

Section: Discussionmentioning

confidence: 97%

“…Given the many downstream effects of FcR activation, identifying the sources of this activation may help limit aberrant macrophage activity. Recent studies have shown a prominent B cell and plasma cell signature in HS lesions with increased immunoglobulin production ( 23 , 50 ). Together with our data, this may indicate significant cross-talk between B cells/plasma cells and monocytes/macrophages in HS via immunoglobulin binding to FcR.…”

Section: Discussionmentioning

confidence: 99%

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Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With M1 Macrophage Polarization in Hidradenitis Suppurativa

et al. 2021

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Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent abscesses, nodules, and sinus tracts in areas of high hair follicle and sweat gland density. These sinus tracts can present with purulent drainage and scar formation. Dysregulation of multiple immune pathways drives the complexity of HS pathogenesis and may account for the heterogeneity of treatment response in HS patients. Using transcriptomic approaches, including single-cell sequencing and protein analysis, we here characterize the innate inflammatory landscape of HS lesions. We identified a shared upregulation of genes involved in interferon (IFN) and antimicrobial defense signaling through transcriptomic overlap analysis of differentially expressed genes (DEGs) in datasets from HS skin, diabetic foot ulcers (DFUs), and the inflammatory stage of normal healing wounds. Overlap analysis between HS- and DFU-specific DEGs revealed an enrichment of gene signatures associated with monocyte/macrophage functions. Single-cell RNA sequencing further revealed monocytes/macrophages with polarization toward a pro-inflammatory M1-like phenotype and increased effector function, including antiviral immunity, phagocytosis, respiratory burst, and antibody-dependent cellular cytotoxicity. Specifically, we identified the STAT1/IFN-signaling axis and the associated IFN-stimulated genes as central players in monocyte/macrophage dysregulation. Our data indicate that monocytes/macrophages are a potential pivotal player in HS pathogenesis and their pathways may serve as therapeutic targets and biomarkers in HS treatment.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With M1 Macrophage Polarization in Hidradenitis Suppurativa

et al. 2021

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“…Transcriptomic analysis showed a marked increase in the expression of CXCL13, which is dominant driver of memory B cell infiltration into tissues, in HS lesional skin 51 …”

Section: Receptorsmentioning

confidence: 99%

Target molecules for future hidradenitis suppurativa treatment

Zouboulis

Frew

Giamarellos‐Bourboulis

et al. 2021

Experimental Dermatology

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The registration of the tumour necrosis factor‐α inhibitor adalimumab in 2015 was a major step forward in the treatment of hidradenitis suppurativa/acne inversa (HS). However, it soon became evident that the effectiveness of adalimumab in daily practice was highly variable. A significant unmet medical need of HS patients remained, and the search for novel therapeutic targets was intensified. During the 10th European Hidradenitis Suppurativa Foundation (EHSF) e.V. Conference, reknown international HS investigators virtually presented and discussed the published data on these potential target molecules for future HS treatment. This article addresses the most promising molecules currently under investigation from a pathophysiological and clinical point of view. With phase III trials ongoing, the anti‐ interleukin (IL)‐17 biologics bimekizumab and secukinumab are in the most advanced stage of clinical development showing promising results. In addition, targeting IL‐1α with bermekimab has shown encouraging results in two clinical trials. Directing treatment at neutrophil recruitment and activation by targeting IL‐36 with spesolimab fits well in the pathogenic concept of HS and clinical phase II trial results are pending. In contrast to in situ evidence, Complement 5a (C5a) and C5a receptor blockade have only shown greater clinical benefit in patients with severe HS. Inhibition of Janus kinase (JAK) 1 signalling in HS showed clinical efficacy only in the highest dosage, highlighting that careful surveillance of the balance between safety and efficacy of JAK inhibition is warranted. Overall, clinical efficacies of all novel treatments reported so far are modest. To guide drug development, more and better‐defined translational data on the pathogenesis of this severe and enigmatic inflammatory skin disease are required.

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“…A broader understanding of B-cell subsets in healthy skin and how they traffic or proliferate in response to inflammation also may be critical to understanding and treating skin inflammatory conditions with limited therapeutic options, such as hidradenitis suppurativa (HS). Recently, memory B cells have been reported to be expanded in HS skin, especially during active inflammatory disease states (Gudjonsson et al, 2020;Lowe et al, 2020). Discerning whether the B-cell lineages present in HS skin are pathogenic drivers of inflammation or proliferate in response to inflammation will support rational therapeutic design.…”

Section: Homing Of Bregs To Inflamed Skinmentioning

confidence: 99%

B Home or You Are In Trouble: B Cell Integrin—Mediated Recruitment Attenuates Skin Inflammation

Moreau

Lowe

2021

Journal of Investigative Dermatology

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B cells were long presumed to be a minor and functionally unimportant component of cutaneous immunobiology. However, it is now clear that these lymphocytes are present in healthy skin and accumulate during inflammatory disease. Aira and Debes (2021) identify ⍺4b1 integrinemediated recruitment of IL-10 þ B cells as a key pathway in attenuating skin inflammation. Their work provides valuable insight into the potential for B cells to regulate skin pathology.

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Immunopathogenesis of hidradenitis suppurativa and response to anti–TNF-α therapy

Cited by 97 publications

References 83 publications

Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With M1 Macrophage Polarization in Hidradenitis Suppurativa

Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With M1 Macrophage Polarization in Hidradenitis Suppurativa

Target molecules for future hidradenitis suppurativa treatment

B Home or You Are In Trouble: B Cell Integrin—Mediated Recruitment Attenuates Skin Inflammation

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