Neutrophils in generalized pustular psoriasis: Key players in disease progression

To the Editor: Generalized pustular psoriasis (GPP) is a rare and highly heterogeneous autoinflammatory skin disease characterized by neutrophil infiltration of the epidermis. Recent advances have highlighted neutrophils as central drivers of GPP pathogenesis through multifaceted mechanisms. The pathogenesis of GPP involves a synergistic interplay between genetic predisposition and environmental triggers. Key genetic drivers of this disorder include mutations in the IL36RN, CARD14, TNIP1, BTN3A3, AP1S3, and SERPINA3 genes, which promote the onset of GPP via the dysregulation of interleukin (IL)-36 production.[1,2] Environmental triggers encompass infection, hypocalcemia, medication regimens (e.g., abrupt glucocorticoid withdrawal), and pregnancy.[1] A notable example by Sugiura et al[3] highlights this interaction: monozygotic twins with compound heterozygous IL36RN mutations developed GPP after amoxicillin exposure. This suggested that β-lactam antibiotics (e.g., amoxicillin) may synergize with bacterial infections to activate cutaneous inflammatory cells, thereby triggering excessive IL-36 production. In genetically predisposed individuals with IL36RN mutations, hypersensitivity to IL-36 signaling leads to uncontrolled neutrophil recruitment and systemic pustular eruptions. Mechanistically, genetic and environmental factors activate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/ mitogen-activated protein kinase (MAPK) pathways in keratinocytes, driving IL-36 and neutrophil chemokines (CXCL1/8, CCL20). This cascade promotes epidermal neutrophil infiltration and characteristic “pus lake” formation [Figure 1A].[1]Figure 1: (A) Recruitment of neutrophil in GPP. Under the influence of external pathological environmental factors, mutations occur in genes such as IL36RN, CARD14, and AP1S3 in patients with GPP, leading to the overactivation of the NF-κB and MAPK pathways in keratinocytes. This, in turn, results in increased transcription of IL-36. The IL-36 precursor is converted into mature IL-36 through the action of various granzymes. The activation of IL-36 positively feeds back to promote the release of neutrophil chemotactic factors such as CXCL1, CXCL2, and CXCL8 from keratinocytes, which facilitates the accumulation of neutrophils towards the epidermis, ultimately forming sterile pustules. Furthermore, neutrophils can promote T-cell activation, and the activated T-cells in turn stimulate keratinocytes to release neutrophil chemotactic factors, further facilitating neutrophil accumulation. (B) The dual roles of NETs in GPP. IL-36α, IL-36β, and IL-36γ interact with the IL-36 receptor on keratinocytes, activating the MAPK and NF-κB pathways, which promote the release of IL-36 precursors and the secretion of chemokines such as CXCL1, CXCL2, and CXCL8 to recruit neutrophils. Granzymes from neutrophils can be released extracellularly through a soluble pathway or attached to NETs, where they cleave and activate IL-36 precursors, facilitating the progression of GPP. NETs also play a role in restricting inflammation: on the one hand, they promote the activation of IL-36Ra to inhibit IL-36 secretion; on the other hand, aggregated NETs degrade inflammatory mediators, thereby suppressing inflammation (By Figdraw). GPP: Generalized pustular psoriasis; HSP70: Heat shock protein 70; IL: Interleukin; MAPK: Mitogen-activated protein kinase; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NET: neutrophil extracellular trap; TLR4: Toll-like receptor 4.TLR8-activated neutrophils secrete IL-23 which drives T helper 17 cell (Th17) differentiation.[4] This process is amplified by neutrophil autocrine signaling via IL-23R, which further induces IL-17A and IL-22 production.[5] In addition, epidermal neutrophil infiltration induces keratinocyte stress, activating heat shock protein 70 (HSP70)/Toll-like receptor 4 (TLR4) signaling to further boost IL-23 release.[6] Neutrophils can therefore promote the production of IL-23, thereby regulating the IL-23/IL-17 axis. Contrary to prior views that Th17 cells were the primary source, neutrophils have now been found to constitute the primary cellular origin of IL-17A in GPP lesions.[7] Neutrophil-derived IL-17A can activate adaptive immune pathways in GPP skin and upregulate keratinocyte chemokines to sustain neutrophil recruitment and epidermal inflammation.[7] Topical imiquimod induces psoriasis-like dermatitis in C57BL/6 mice and elevated IL-17A/IL-23. These effects were reported to be suppressed in IL-36R-deficient mice but exacerbated in IL-36RN-deficient mice,[8] indicating that IL-36 cytokines regulate the IL-23/IL-17 axis and are critical in psoriatic inflammation. IL-36 stimulates autocrine cytokine production, amplifies IL-17-mediated antimicrobial peptides, and activates adaptive immunity.[9] Conversely, IL-17 upregulates IL-36α/β/γ in psoriatic keratinocytes.[9] Hence, the IL-36/neutrophil axis drives pathogenesis through circuits that are interconnected with the IL-23/IL-17 axis. Neutrophils bridge the innate and adaptive immunity through IL-36-driven innate responses and IL-23/IL-17 secretion. Neutrophils play a crucial role in GPP through the release of granzymes and the formation of neutrophil extracellular traps (NETs). Neutrophil granule proteases (elastase, proteinase 3, cathepsin G) drive GPP pathogenesis through proteolytic activation of IL-36 cytokines[1]: Elastase preferentially processes IL-36γ, whereas cathepsin G activates IL-36β, amplifying IL-36 activity by up to 500-fold. These proteases also truncate CXCL5/CXCL8, thereby enhancing neutrophil chemotaxis. Myeloperoxidase (MPO) deficiency in GPP neutrophils triggers the compensatory upregulation of IL-36-activating proteases and causes elevated CD47 expression, thus delaying phagocytic clearance and prolonging inflammation.[10] In summary, granule proteases critically drive GPP pathogenesis by activating IL-36, establishing a self-amplifying inflammatory loop. NETs, composed of DNA/RNA scaffolds and granular proteins (e.g., elastase, myeloperoxidase), play a dual role in GPP. Although excessive NETs exacerbate psoriasis by activating keratinocytes and Th17 cells,[11] their precise role in GPP pathogenesis remains unclear. NETs exhibit context-dependent functions: they amplify inflammation by recruiting enzymes that activate IL-1 family cytokines (e.g., IL-36),[1] yet paradoxically also resolve inflammation via the protease-mediated degradation of inflammatory mediators.[12] This duality likely stems from neutrophil heterogeneity. For instance, OLFM4, a neutrophil-specific granule protein, is predominantly found in NETs, allowing neutrophils to be classified into OLFM4+ and OLFM4– subsets. Compared with normal controls, the number of OLFM4+ neutrophils is significantly increased in patients with GPP and positively correlates with disease severity.[13] Furthermore, prior studies have shown that CXCR4hi neutrophils exhibit a proinflammatory phenotype and an increased capacity to release NETs compared with CXCR4low neutrophils, promoting the recruitment of inflammatory cells.[14] Based on neutrophil density, they can be divided into low-density and high-density. Low-density neutrophils (LDNs) have an increased capacity to release NETs and are significantly elevated in the peripheral blood of patients with GPP.[15] In contrast, high-density neutrophils (HDNs) can produce aggregated NETs (aggNETs), which degrade inflammatory mediators, suggesting their anti-inflammatory potential[12] [Figure 1B]. Defective aggNET formation may impair inflammation resolution, leading to the persistent existence of neutrophils and chronic inflammation. Hence, NETs in GPP act as a double-edged sword as their pro- or anti-inflammatory effects are dictated by neutrophil subset dynamics. Recent advances in GPP management have highlighted IL-36 pathway inhibitors as transformative therapies [Supplemental Table 1, https://links.lww.com/CM9/C478]: Spesolimab, the first FDA/EMA-approved IL-36R antagonist, demonstrated rapid lesion clearance (>50% by day 7) in phase II trials and superior flare prevention in phase III studies. Novel agents such as recibokibart and imsidolimab have further validated this therapeutic axis, though 15–20% of patients with MPO mutations exhibit primary resistance. Given neutrophils’ pathogenic role in GPP, emerging therapeutic strategies have targeted neutrophils and shown promising results. Neutrophil-centric therapeutic approaches can be stratified by molecular target [Supplemental Table 2, https://links.lww.com/CM9/C478], i.e., “NETosis modulation” through PAD4 inhibitors (e.g., Cl-amidine) or DNase I disruption of pathogenic NET formation. Both of these approaches show preclinical efficacy against neutrophilic inflammation. Notably, however, the clinical utility of DNase I is limited by rapid serum degradation, necessitating nano-engineering for sustained bioavailability. “Oxidative stress regulation” through NOX2 inhibitors (e.g., Cyr5099) attenuates ROS-driven tissue damage in murine arthritis models, yet has off-target effect risks due to the dual roles of ROS in inflammation and host defense. “Migration blockade” through CXCR2 antagonists (e.g., AZD5069) inhibits IL-8-mediated neutrophil recruitment, but its phase II trials have reported increased respiratory disorders (34.6% vs. 19.2% placebo), highlighting immunosuppression risks. “Effector function inhibition” that targets neutrophil elastase (e.g., AZD9668) reduces protease-mediated damage in bronchiectasis but has poor cutaneous penetration, requiring advanced topical delivery systems. Critical knowledge gaps persist, including spatial heterogeneity of neutrophil subsets in lesions and risks of off-target toxicity. Future priorities include developing skin-selective delivery systems, defining neutrophil subpopulation biomarkers. Although neutrophil-targeted therapies remain investigational, their mechanistic precision positions them as key candidates for GPP. Conflicts of interest None.