The role of fibroblast-neutrophil crosstalk in the pathogenesis of inflammatory diseases: a multi-tissue perspective

Abstract

Neutrophil-fibroblast crosstalk drives inflammatory pathology across organ systems through both shared and tissue-specific mechanisms. This review synthesizes evidence from skin, lung, gut, cardiovascular, joint, sinus, and oral diseases, revealing conserved molecular pathways where fibroblasts secrete chemokines (CXCL1/8/12) to recruit neutrophils, which, in turn, release neutrophil extracellular traps (NETs), elastase, and cytokines to modulate fibroblast function. Additionally, we identify critical tissue-specific differences, including the predominance of IL-36 signaling in COPD, IL-17-carrying NETs in systemic lupus erythematosus (SLE) and pulmonary fibrosis, and specialized fibroblast subpopulations, such as IDO1+ cells in CRSwNP and TNFRSF21+ cells in periodontitis. Translational insights highlight the therapeutic potential of targeting IL-17, NETs, and fibroblast subpopulations, though tissue-specific risks necessitate precision strategies. Future therapeutic efforts should focus on developing precision-targeted interventions that address organ-specific mechanisms to overcome treatment resistance in inflammatory disorders.

Keywords: NETs; chemokines; cytokines; fibroblasts; inflammation; neutrophils.

Figure 1

A conserved inflammatory axis is evident throughout all tissues: under stimulation by upstream inflammatory mediators such as IL-17 and IL-1β, fibroblasts secrete chemokines including CXCL1, CXCL2, CXCL8, and CXCL12, which bind to neutrophil surface receptors (primarily CXCR2 and CXCR4) to orchestrate neutrophil recruitment and infiltration into inflammatory sites. Reciprocally, neutrophils modulate fibroblast phenotype and function through the release of NETs, elastase, and pro-inflammatory cytokines, establishing a positive feedback loop that perpetuates and amplifies inflammatory responses. Created in BioRender. cai, c. (2025) https://BioRender.com/6hm5abd.

Figure 2

Tissue-specific characteristics in fibroblast-neutrophil communication in inflammatory diseases. This figure illustrates the distinct tissue-specific mechanisms through which fibroblasts and neutrophils interact in the pathogenesis of inflammatory diseases. In chronic obstructive pulmonary disease (COPD), IL-36γ primarily stimulates lung fibroblasts to release IL-1, CXCL1, GM-CSF, and matrix metalloproteinases, thereby promoting both inflammation and fibrosis. In systemic lupus erythematosus (SLE) skin lesions and pulmonary fibrosis, IL-17-containing neutrophil extracellular traps (NETs) activate fibroblasts to produce collagen, contributing to tissue remodeling and fibrosis. Organ-specific fibroblast subpopulations exhibit unique patterns in their interaction with neutrophils: IDO1+ fibroblasts in chronic rhinosinusitis with nasal polyps (CRSwNP) promote neutrophil recruitment by secreting CXCL1/2/3/5/6/8, while TNFRSF21+ fibroblasts in periodontitis facilitate neutrophil infiltration through a distinct chemokine profile. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) present NET-derived citrullinated peptides via MHC-II, bridging innate and adaptive immunity and promoting chronic inflammation. In inflammatory bowel disease (IBD), NRG1+IL1R1+ fibroblasts are impaired in their reparative functions when exposed to IL-1β released by neutrophils, which exacerbates intestinal inflammation. These tissue-specific interactions are further influenced by systemic factors such as diabetes, which enhances the production of CXCL1/12 through insulin signaling pathways in gingival fibroblasts, and environmental factors such as circadian rhythm disruption, which amplifies CXCL5-mediated neutrophil recruitment in lung fibroblasts through hyperactivation of the NF-κB pathway. Created in BioRender. cai, c. (2025) https://BioRender.com/dovm1ct.