Monocytes develop from hematopoietic stem cells; migrate into the tissue, where they undergo a stimulation-dependent and tissue specific differentiation into macrophages imprinting specific inflammatory functions. The development of inflammatory functions during differentiation of progenitor cells into macrophages remained incompletely understood. We intended to identify regulatory factors driving monocyte/macrophage differentiation. A Genome-wide CRISPR/Cas9 knockout screen (GeCKO) in ER-HoxB8 macrophages was used to identify key drivers of macrophage differentiation which were verified in independent knock-out and knock-in cells. Immunophenotyping was studied by FACS, morphology and migration by fluorescence microscopy, the inflammatory response by ELISA. Transcriptomic data were obtained by next generation mRNA sequencing and validated by quantitative polymerase chain reaction and immunoblotting. Genome-wide CRISPR/Cas9 knockout screen identified the cytosolic cytoskeleton-associated adaptor molecule PSTPIP1 (proline-serine-threonine phosphatase interacting protein 1) as a regulatory factor of macrophage differentiation. Interestingly, mutations in PSTPIP1 cause autoinflammatory disorders (PAPA syndrome). Deletion of PSTPIP1 resulted in hampered differentiation, decreased inflammatory response, changed morphology, altered cell adhesion and migration properties. PSTPIP1 is a regulator of Pyrin inflammasome activity which drives autoinflammation in familial Mediterranean fever (FMF). Deletion of Pyrin also resulted in a strong alteration of cellular dynamics in macrophages. PSTPIP1 and Pyrin are crucial factors in macrophage differentiation. Their deletion or mutation resulted in a hampered differentiation of macrophages resulting in strong morphological alterations and impacting phagocyte key functions as adhesion and migration. Impaired differentiation of macrophages may represent a significant factor in the pathophysiology of autoinflammatory diseases like FMF and PAPA.

Hidradenitis suppurativa (HS) and pyoderma gangrenosum (PG) are chronic neutrophilic dermatoses characterized by dysregulated inflammation. Their coexistence in adults has been reported, but this has not been well documented in pediatric populations. To characterize the overlap, clinical characteristics, and treatment options for pediatric patients with concurrent HS and PG. We conducted a retrospective case series of pediatric patients ages 3 to 17 with clinical diagnoses of HS and PG at The Hospital for Sick Children between January 2015 and January 2022. Demographic, clinical, laboratory, genetic, and treatment data were extracted from electronic medical records and analyzed descriptively. Seven of 122 pediatric HS patients (5.7%) had concurrent PG. HS onset preceded PG in all cases, with mean onset ages of 11.6 and 16.1 years, respectively. The cohort had a slight male predominance (57%) and high rates of comorbidities, including obesity (71.4%) and acne conglobata (42.9%). Elevated erythrocyte sedimentation rate (ESR) (mean 56.9 mm/hour) was a significant predictor of HS severity (P = .027). Three patients had autoinflammatory gene variants, and 57.1% met criteria for PASH or PAPA syndrome. Cytokine profiling revealed elevated IL-1β and IL-6 in select cases. Three of 4 patients who underwent incision and drainage for HS developed PG at the surgical sites. Pediatric patients with HS-PG may represent a distinct, severe inflammatory subset. Further investigation is needed to define risk factors, inflammatory biomarkers, and optimal treatment strategies in this rare overlap population.

Notch signaling is an evolutionarily conserved, multifunctional pathway involved in cell fate determination and immune modulation and contributes to the pathogenesis of autoinflammatory diseases. Emerging evidence reveals a bidirectional interaction between Notch and the gut microbiota (GM), whereby GM composition is capable of modulating Notch signaling through the binding of microbial elements to Notch receptors, leading to immune modulation. Furthermore, Notch regulates the GM by promoting SCFA-producing bacteria while suppressing proinflammatory strains. Beneficial microbes, such as Lactobacillus and Akkermansia muciniphila, modulate Notch and reduce proinflammatory cytokine production (such as IL-6 and TNF-α). The interaction between GM and Notch can either amplify or attenuate inflammatory pathways in inflammatory bowel diseases (IBDs), Behçet's disease, and PAPA syndrome. Together, these findings provide novel therapeutic perspectives for autoinflammatory diseases by targeting the GM via probiotics or inhibiting Notch signaling. This review focuses on Notch-GM crosstalk and how GM-based and/or Notch-targeted approaches may modulate immune responses and promote better clinical outcomes.

Neutrophils have both antimicrobial ability and pathogenic effect in the immune system, neutrophil extracellular traps (NETs) formation is one of the representative behaviors of their dual role. NETs formation was triggered by pathogen-related components and pathogen non-related proteins as cytokines to exert its effector functions. Recent studies indicate that the pathogenicity of NETs contributed to several skin diseases such as psoriasis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and neutrophilic dermatosis. Especially in neutrophilic dermatosis, a heterogeneous group of inflammatory skin disorders characterized with sterile neutrophilic infiltrate on dermis, NETs formation was reported as the way of participation of neutrophils in the pathogenesis of these diseases. In this review, we describe the different processes of NETs formation, then summarized the most recent updates about the pathogenesis of neutrophilic dermatosis and the participation of NETs, including pyoderma gangrenosum and PAPA syndrome, Behçet syndrome, hidradenitis suppurativa, Sweet Syndrome, pustular dermatosis and other neutrophilic dermatosis. Furthermore, we discuss the link between NETs formation and the development of neutrophilic dermatosis.