Neutrophilic granulocyte-derived B-cell activating factor supports B cells in skin lesions in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by painful inflamed nodules, abscesses, and pus-draining tunnels appearing in axillary, inguinal, and perianal skin areas. HS lesions contain various types of immigrated immune cells. This study aimed to characterize mediators that support lesional B/plasma cell persistence in HS. Skin samples from several cohorts of HS patients and control cohorts were assessed by mRNA sequencing, quantitative PCR on reverse-transcribed RNA, flow cytometry, and immunohistofluorescence. Blood plasma and cultured skin biopsy samples, keratinocytes, dermal fibroblasts, neutrophilic granulocytes (neutrophils), monocytes, and B cells were analyzed. Complex systems biology approaches were used to evaluate bulk and single-cell RNA sequencing data. Proportions of B/plasma cells, neutrophils, CD8+ T cells, and M0 and M1 macrophages were elevated in HS lesions compared to skin of healthy and perilesional intertriginous areas. There was an association between B/plasma cells, neutrophils, and B-cell activating factor (BAFF, aka TNFSF13B). BAFF was abundant in HS lesions, particularly in nodules and abscesses. Among the cell types present in HS lesions, myeloid cells were the main BAFF producers. Mechanistically, granulocyte colony-stimulating factor in the presence of bacterial products was the major stimulus for neutrophils' BAFF secretion. Lesional upregulation of BAFF receptors was attributed to B cells (TNFRSF13C/BAFFR and TNFRSF13B/TACI) and plasma cells (TNFRSF17/BCMA). Characterization of the lesional BAFF pathway revealed molecules involved in migration/adhesion (eg, CXCR4, CD37, CD53, SELL), proliferation/survival (eg, BST2), activation (eg, KLF2, PRKCB), and reactive oxygen species production (eg, NCF1, CYBC1) of B/plasma cells. Neutrophil-derived BAFF supports B/plasma cell persistence and function in HS lesions.

Sabat R ，Šimaitė D ，Gudjonsson JE ，Brembach TC ，Witte K ，Krause T ，Kokolakis G ，Bartnik E ，Nikolaou C ，Rill N ，Coulibaly B ，Levin C ，Herrmann M ，Salinas G ，Leeuw T ，Volk HD ，Ghoreschi K ，Wolk K ... -  《-》

Activity and components of the granulocyte colony-stimulating factor pathway in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease, characterized by painful, purulent and destructive skin alterations in intertriginous areas. We investigated the expression and role in HS of granulocyte colony-stimulating factor (G-CSF), the regulator of neutrophil biology, as clinical signs of a neutrophilic granulocyte-driven inflammation are distinctive in the disease. Skin and blood samples obtained from different cohorts of patients with HS and control individuals were assessed by RNA sequencing, quantitative polymerase chain reaction on reverse transcribed mRNA, and/or enzyme-linked immunosorbent assay. Mechanistic studies using keratinocytes, dermal fibroblasts, immune cell populations and skin biopsies were performed. G-CSF was abundant in HS skin, particularly in inflamed nodules and abscesses. Its levels even exceeded those found in other inflammatory skin diseases. Interleukin (IL)-1 and IL-17, respectively, induced G-CSF production by fibroblasts and keratinocytes. These effects were enhanced by tumour necrosis factor (TNF)-α and IL-36. Accordingly, fibroblasts separated from HS lesions expressed G-CSF, and IL-1 receptor antagonist reduced G-CSF levels in explanted HS skin. G-CSF blood levels positively correlated with severity of HS. Elevated lesional G-CSF receptor levels were linked to upregulation of molecules that contribute to prolonged activation of neutrophils by components of bacteria and damaged host cells [formyl peptide receptor 1 (FPR1), FPR2 and free fatty acid receptor 2 (FFAR2)], neutrophil survival [TNF receptor superfamily member 10C (TNFRSF10C/TRAIL-R3) and TNF receptor superfamily member 6B], kinases (tyrosine-protein kinase HCK and hexokinase 3), and skin destruction [MMP25 (matrix metalloproteinase 25) and ADAM8 (disintegrin and metalloproteinase domain-containing protein 8)]. G-CSF elevated the expression of FPR1, FFAR2, and TNFRSF10C/TRAIL-R3 in neutrophils and synergized with bacterial components to induce skin-destructive enzymes. The G-CSF pathway engages both tissue and immune cells, is strongly activated in HS lesions, and offers the opportunity to target the neutrophil-driven inflammation.

Wolk K ，Brembach TC ，Šimaitė D ，Bartnik E ，Cucinotta S ，Pokrywka A ，Irmer ML ，Triebus J ，Witte-Händel E ，Salinas G ，Leeuw T ，Volk HD ，Ghoreschi K ，Sabat R ... -  《-》

Phytotherapeuthics Affecting the IL-1/IL-17/G-CSF Axis: A Complementary Treatment Option for Hidradenitis Suppurativa?

Witte K ，Sabat R ，Witte-Händel E ，Ghoreschi K ，Wolk K ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

High inflammation in hidradenitis suppurativa extends to perilesional skin and can be subdivided by lipocalin-2 expression.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease presenting with diverse manifestations ranging from nodules and abscesses to draining tunnels. Whether the underlying inflammation from lesions extends to relatively healthy-appearing adjacent perilesional and distant nonlesional skin has not been systematically evaluated. We sought to characterize lesional, perilesional, and nonlesional skin in patients with HS. Skin biopsy samples were collected under ultrasound guidance from patients with active, untreated moderate-to-severe HS. Site-matched control biopsy samples from healthy volunteers were used for comparison. RNA sequencing demonstrated that HS skin clustered separately from healthy control skin, with perilesional and lesion skin clustering together and away from nonlesional skin. Immunohistochemistry analysis identified psoriasiform hyperplasia with keratin 16 positivity in both perilesional and lesional skin, with comparable levels of CD3+, CD11c+, and neutrophil elastase-positive cellular infiltration. There was a marked upregulation of IL-17 signaling in perilesional and lesional skin. HS samples clustered on the basis of expression of lipocalin-2 (LCN2), with samples characterized by high LCN2 expression in the skin exhibiting a differing transcriptomic profile with significantly higher overall inflammation than that of skin characterized by low LCN2 levels. Perilesional HS skin has a transcriptomic and molecular profile comparable to that of lesional skin. HS can be grouped into 2 distinct subtypes based on molecular levels of LCN2 in the skin, with the LCN2-high subtype exhibiting an overall higher inflammatory burden and an upregulation of targetable cytokines. To our knowledge, this is the first study to characterize a unique HS subtype (and a potential endotype) that may guide future therapeutic targets.

Navrazhina K ，Garcet S ，Zheng X ，Hur HB ，Frew JW ，Krueger JG ... -  《-》

B-cell maturation antigen (BCMA) activation exerts specific proinflammatory effects in normal human keratinocytes and is preferentially expressed in inflammatory skin pathologies.

Alexaki VI ，Pelekanou V ，Notas G ，Venihaki M ，Kampa M ，Dessirier V ，Sabour-Alaoui S ，Stathopoulos EN ，Tsapis A ，Castanas E ... -  《-》