Summary 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. What's already known about this topic? Acne inversa (AI) is a painful and debilitating chronic inflammatory disease with unknown pathogenesis and a profound medical need. The efficacy of the recently approved anti‐tumour necrosis factor (TNF)‐α treatment suggests an important role for TNF‐α in the maintenance of AI lesions. Physicians currently lack a commonly used dynamic scoring system and a blood biomarker for assessing the inflammatory activity of the skin alterations. What does this study add? Lipocalin‐2 (LCN2) is one of the most significantly upregulated blood parameters in patients with AI. In AI lesions, granulocytes and, to a lower extent, keratinocytes produce LCN2. While TNF‐α seemed to be the sole inducer of granulocyte LCN2, interleukin (IL)‐1β, IL‐17 and TNF‐α provoke keratinocyte LCN2 production. In AI, LCN2 blood levels positively correlate with Sartorius score and with TNF‐α blood levels. What is the translational message? Quantifying LCN2 blood levels may be used for objective estimation of disease severity in patients with AI. LCN2 blood levels should be tested as a predictor for therapy decisions and assessment of therapy response (especially for anti‐TNF‐α treatment). Anti‐TNF‐α treatment may interrupt the suggested vicious circle comprising TNF‐α, neutrophilic granulocytes, and LCN2, that contributes to the high cutaneous number of neutrophils, clinically evident as pus in AI. Linked Comment: Mössner. Br J Dermatol 2017; 177:1162–1164. Respond to this article