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Summary: Background: Hidradenitis suppurativa (HS) is a chronic inflammatory disease, characterized by painful, purulent and destructive skin alterations in intertriginous areas. Objectives: 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. Methods: 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. Results: 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. Conclusions: 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. What is already known about this topic? Hidradenitis suppurativa (HS) is a chronic debilitating skin disorder with a very high, unmet medical need.The diseased skin in patients with HS shows distinct features of a neutrophil‐driven inflammation (e.g. abscess formation, purulent discharge).Granulocyte colony‐stimulating factor (G‐CSF) is the major regulator of neutrophil development, survival and function. What does this study add? HS lesions show highly increased levels of G‐CSF and its receptor.Major G‐CSF inducers are interleukin (IL)‐1β and IL‐17.In neutrophils, G‐CSF upregulates receptors for components of bacteria and damaged host cells, decoy receptors for apoptosis inducers and proteases.The production of skin‐destructive enzymes induced by bacterial components is strengthened by G‐CSF in neutrophils.G‐CSF inducers and molecules upregulated by G‐CSF in neutrophils in vitro are abundant in HS lesions. What is the translational message? G‐CSF is the central element of a pathogenetic pathway in HS.The G‐CSF pathway may contribute to the persistence of abscesses, purulent secretion and progressive skin structure destruction.Targeting G‐CSF or its pathway elements may represent an approach for the treatment of HS and other conditions with neutrophil‐driven inflammation and skin destruction. Linked Comment: E.J. Giamarellos‐Bourboulis. Br J Dermatol 2021; 185:15–16. [ABSTRACT FROM AUTHOR]

Summary: Hidradenitis suppurativa (HS) is a chronic inflammatory disorder. Patients develop inflamed nodules and abscesses and, at later stages of disease, epithelialized tunnels and scars in skinfolds of axillary, inguinal, gluteal and perianal areas. Quality of life is affected due to severe pain, purulent secretion, restricted mobility and systemic involvement. Genetics and lifestyle factors including smoking and obesity contribute to the development of HS. These factors lead to microbiome alteration, subclinical inflammation around the terminal hair follicles, and infundibular hyperkeratosis, resulting in plugging and rupture of the follicles. Cell‐damage‐associated molecules and propagating bacteria trigger inflammation and lead to massive immune cell infiltration that clinically manifests as inflamed nodules and abscesses. The immune system plays a key role also in the progression and chronification of skin alterations. Innate proinflammatory cytokines (e.g. interleukin‐1β and tumour necrosis factor‐α), mediators of activated T helper (Th)1 and Th17 cells (e.g. interleukin‐17 and interferon‐γ), and effector mechanisms of neutrophilic granulocytes, macrophages and plasma cells are involved. Simultaneously, skin lesions contain anti‐inflammatory mediators (e.g. interleukin‐10) and show limited activity of Th22 and regulatory T cells. The inflammatory vicious circle finally results in pain, purulence, tissue destruction and scarring. Chronic inflammation in patients with HS is also frequently detected in organs other than the skin, as indicated by their comorbidities. All these aspects represent a challenge for the development of therapeutic approaches, which are urgently needed for this debilitating disease. This scholarly review focuses on the causes and pathogenetic mechanisms of HS and the potential therapeutic value of this knowledge. [ABSTRACT FROM AUTHOR]

Summary: Background: Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal gammopathy, which manifest mostly in the second half of life. It involves overactivation of the interleukin (IL)‐1 system, but the exact pathophysiological pathways remain largely unknown. Objectives: To identify and characterize the pathogenetic players in SchS. Methods: Blood parameters were quantified in patients with SchS compared with healthy controls and patients with psoriasis and hidradenitis suppurativa using enzyme‐linked immunosorbent assay (ELISA). CCL2 expression in cultured primary cells was analysed by quantitative reverse‐transcriptase polymerase chain reaction and ELISA. Results: CCL2, a chemoattractant for monocytic and further mononuclear immune cells, was found to be significantly elevated in patients with SchS. CCL2 levels showed a positive association with global disease activity, especially with bone pain, but not disease duration, gammopathy, neutrophilia or skin disease. In vitro stimulation assays demonstrated a strong CCL2 production capacity of mononuclear immune cells and fibroblasts, but not epithelial or endothelial cells. Among a range of inflammatory mediators, only IL‐1β (immune cells, fibroblasts) and tumour necrosis factor (TNF)‐α (fibroblasts) were important CCL2 inducers. TNF‐α, but not IL‐17, strengthened the CCL2‐inducing effect of IL‐1β in fibroblasts. Accordingly, CCL2 levels positively correlated with both TNF‐α and IL‐1β serum levels in patients with SchS. Therapeutic IL‐1β blockade decreased CCL2 blood levels in these patients as early as 1 week after the initiation of treatment. Conclusions: CCL2 may be an important component of the pathogenetic cascade leading to bone alterations, and a suitable marker of disease activity in patients with SchS. What's already known about this topic?Schnitzler syndrome (SchS) is a very rare acquired autoinflammatory disease, clinically characterized by urticarial exanthema, arthralgia and osteosclerosis, and episodes of fever.The pathogenesis involves overactivation of the interleukin‐1 system.The exact pathogenetic pathways are mostly unknown, and biomarkers are not available to assess the inflammatory activity in SchS. What does this study add? The chemokine CCL2 is a marker of SchS; its blood levels are significantly upregulated and linked to global disease activity and early therapy response in patients with SchS.While no clear relationship with patients' urticarial exanthema was detected, CCL2 may be involved in bone alterations in these patients.The cellular sources of CCL2 include mononuclear immune cells and fibroblasts.Interleukin‐1β and tumour necrosis factor‐α, blood levels of which correlate with CCL2 levels in patients with SchS, are important CCL2 inducers. What is the translational message? Quantifying CCL2 blood levels may allow the objective estimation of inflammatory disease activity and may help with the therapy decision in patients with SchS.CCL2 may be a key element of the pathogenetic cascades in SchS, especially those important for osteosclerosis. Linked Comment:Kambe and Nguyen. Br J Dermatol 2019; 180:706–707. Respond to this article Plain language summary available online [ABSTRACT FROM AUTHOR]

Background Acne inversa ( AI)/hidradenitis suppurativa is a chronic inflammatory disease characterized by painful axillary, inguinal and perianal skin lesions with deep-seated nodules, abscesses and fistulae. Objectives This study aimed to identify and characterize the key players in AI pathogenesis. Methods Epidemiological and anamnestic data for patients with AI were collected, and blood and skin samples were also taken. Healthy participants and patients with psoriasis served as controls. Assessment of samples and cultures of primary cells was performed by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction on reverse transcribed mRNA, and immunohistochemistry. Results Of 35 mediators quantified in the blood of patients with AI, lipocalin-2 ( LCN2) appeared as one of the most significantly upregulated parameters compared with healthy participants [85·8 ± 12·2 ( n = 18) vs. 41·8 ± 4·2 ( n = 15); P < 0·001]. Strongly elevated LCN2 expression was present in AI lesions, with granulocytes and keratinocytes being sources of this expression. In vitro, these cells upregulated LCN2 production in response to tumour necrosis factor ( TNF)-α, and a positive relationship between systemic TNF-α and LCN2 levels ( rs = 0·55, P = 0·011; n = 20) was evident for AI. LCN2 blood levels correlated with AI disease severity ( rs = 0·65, P < 0·001; n = 29), but not with disease duration, age, sex, body mass index or smoking habit. Detailed analyses revealed a link with the number of skin regions containing nodules and fistulae, but not scars. Conclusions LCN2 might serve as a blood biomarker for the objective assessment of inflammatory activity in AI. We suggest a self-amplification loop comprising TNF-α, neutrophilic granulocytes and LCN2, which contributes to the recurrent skin neutrophil infiltration in AI, clinically evident as pus. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-10 is one of the most crucial immunoregulatory cytokines. Its short-term effects have been analysed extensively, but little is known about its long-term effects. This is of considerable importance, as high systemic IL-10 levels are present for long periods in patients with persistent viral infections, certain cancers and in critical care patients. Our study investigated the effects of the long-term presence of IL-10 on human peripheral blood monocytes. In vitro, IL-10 treatment of these cells for 7 days induced the development of a novel cell type characterized by unique phenotypical and functional characteristics. These cells showed high HLA-DR expression and low expression of CD86 and other co-stimulatory molecules on their surface. The mRNA levels of both HLA-DR and CD86 were high, but no intracellular accumulation of CD86 protein was observed. With respect to its function, these cells showed strongly diminished tumour necrosis factor-α production following lipopolysaccharide stimulation, strongly diminished allogenic CD4+ T cell stimulatory capacity, and even induced a hyporesponsive state in CD4+ T cells. The phenotype remained stable despite the removal of IL-10. In vivo, we found monocytic cells from patients exhibiting this phenotype after long-term IL-10 exposure. These results complement our knowledge further about the biological effects of IL-10 and may provide an explanation for the sustained immunodeficiency in cases of the persistent presence of systemic IL-10. [ABSTRACT FROM AUTHOR]

Linked Article: Krause et al. Br J Dermatol 2019; 180:859–868 [ABSTRACT FROM AUTHOR]

Summary: Schnitzler syndrome is a very rare chronic disease, which usually develops in the second half of life. It appears as skin rashes, muscle/skeletal pain and fever episodes. The trigger and molecular processes in the disease are not understood. However, drugs that inhibit the inflammatory molecule called interleukin‐1ß were found to relieve the disease. The authors of this German study wondered which further molecules are involved in Schnitzler syndrome. For this purpose, a range of molecules with inflammatory properties was quantified in the blood of the patients and, as a comparison, in healthy people and patients with other inflammatory diseases. Patients with Schnitzler syndrome were found to have strongly elevated levels of CCL2, a molecule known to attract inflammatory cells to affected tissues and to have a special role in bone alterations. CCL2 levels were particularly high in severely affected patients, especially those with intense bone pain. In the bone, CCL2 is known to be produced by certain bone‐modifying cells. Laboratory experiments revealed that CCL2 was also highly produced by immune cells and connective tissue cells (fibroblasts). Interleukin‐1ß as well as the inflammatory molecule TNF‐α triggered the production of CCL2 by these cells. When patients were treated with an interleukin‐1ß‐blocking drug, health improvement was paralleled by a drop of CCL2 levels. The authors concluded that in Schnitzler syndrome CCL2 is an important player in the inflammation process in bones and other body sites and may be used in the clinic as an indicator of disease severity. Linked Article: Krause et al. Br J Dermatol 2019; 180:859–868 [ABSTRACT FROM AUTHOR]