Expanded proinflammatory CD4 T cells expressing toll like receptor 4 in trauma associated acute lung injury

Acute lung injury (ALI) is characterised by hypoxia and inflammation that derives from diverse aetiologies. Delineating the molecular pathogeneses may identify treatable subgroups and inform clinical trials. Using a multi-omics approach, we analysed trauma-associated ALI (n = 9), COVID-19 ALI (n = 11), ICU controls (n = 13) using scRNA-seq, serum cytokine profiling, and bronchoalveolar lavage (BAL) microbiome analysis. We identified a population of activated CD4+ T cells expressing Toll-like receptor 4 (TLR4) and downstream NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome complex, predominantly in trauma-associated ALI (23% of CD45+ Cells) compared to COVID-19 ALI (14%) and ICU controls (15%). Serum IL-1RA and IL-6 were upregulated in trauma ALI, along with TLR4-binding ligand hyaluronan. TLR4 expression on CD4+ T cells was confirmed by spectral cytometry. Lung microbiome analysis revealed distinct diversity in trauma-associated ALI compared to COVID-19 ALI. These findings highlight TLR4-mediated inflammation in trauma-associated ALI and suggest potential precision medicine approaches for ALI management. Multi-omic characterisation of the immune landscape in acute lung injury due to trauma and COVID-19. Expanded TLR4-expressing pro-inflammatory CD4 + T cells and associated innate immune signalling are specific to trauma-associated acute lung injury.