T1/T3 pathways and chemokines in mild-to-severe neutrophilic asthma

<bold>Introduction:</bold> T2-low asthma is related to neutrophilic [NEU], paucigranulocytic (low NEU and eosinophils [EOS]) or mixed (both EOS/NEU) inflammation. <bold>Aim:</bold> To identify molecular biomarkers associated to NEU asthma phenotype(s). <bold>Methods:</bold> We selected 59 bronchial biopsies from mild-to-severe asthmatics and stratified, according to bronchial EOS/NEU counts, into NEU (n=31; NEU≥47.17 cells/mm²) and EOS (n=28; EOS>12.45 cells/mm² and NEU<47.17 cells/mm²). NEU group was then divided into intermediate NEU (int-NEU, n=14; NEU≥47.17 cells/mm² and <94.34 cells/mm²) and high NEU (hi-NEU, n=17; NEU≥94.34 cells/mm²). By means of immunohistochemistry (IHC) we assessed the expression of T1/T3 (STAT1, pSTAT1, STAT4, pSTAT4, INF-γ, t-bet, IL-27, ROR-γT) markers and NEU-related chemokines (RANTES, CCR5, NAP-2, GM-CSF, IL-8). Subjects’ clinical/functional data were collected. <bold>Results:</bold> NEU were characterized by the use of a higher dose of ICS, a major frequency of patients on OCS, and more exacerbations [exa]/year than EOS (p<0.05). Stratification by bronchial NEU, revealed that these differences were accountable to hi-NEU. This latter group also showed a longer asthma duration and more atopy and severity than EOS (p<0.05). The comparison between hi-NEU and int-NEU unveiled that hi-NEU had more exa/year, a higher frequency of atopy and more total serum IgE(p<0.05). IHC showed that int-NEU group had increased T1⁺ (IL-27, INF-γ, STAT1), RANTES⁺ and CCR5⁺ cells than EOS (p<0.05). Hi-NEU group had an enrichment of ROR-γT⁺ (transcription factor related to T3 immunity) cells in bronchial mucosa than EOS (p<0.05). <bold>Conclusion:</bold> Upregulation of T1/T3 immunity and NEU-related chemokines differentially modulates NEU inflammation in mild-to-severe asthma.