Adipose Tissue As A Site of Immune Activation and Dysfunction in Individuals with Obesity and Asthma

bioRxiv : the preprint server for biology  ·  2026

Dawn C Newcomb; Alessandra Tomasello; Jean-Philippe Cartailler; Bilgunay Ilkin Safa; LaToya Hannah; Shristi Shrestha; Shahar Hartman; Melissa H Bloodworth; Kevin Niswender; John R Koethe; Samuel Bailin; James Matthew Luther; Nancy J Brown; Mona Mashayekhi; Katherine N Cahill;

HIGHLIGHT

Gene co-expression analysis identified gene modules associated with asthma diagnosis, lung function, and biomarkers of type 2 inflammation were enriched in effector cells.

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ABSTRACT

Obesity increases local inflammatory responses in adipose tissue. Individuals with obesity have increased asthma incidence and severity and reduced responses to asthma therapeutics through unknown mechanisms. To identify mechanisms by which increased fat mass augments asthma pathogenesis, single cell RNA sequencing of the immune-rich stromovascular fraction of subcutaneous adipose tissue was conducted from well-characterized adults with obesity-associated asthma matched to adults without asthma. Individuals with asthma had increased abundance of perivascular macrophages and lymphoid-associated macrophages (LAMs) and reduced abundance of classical monocytes and CD4+ and CD8+ naïve T cells. Pseudo-bulk differential expression (DE) identified upregulation of cellular metabolism, specifically oxidative phosphorylation, and decreased immune homeostatic pathways in asthma across immune cell subsets. Cell type specific DE analysis of effector cell subtypes identified significant induction of metallothionein gene expression in asthma, a signature of immune cell dysfunction characterized by both an activation and exhaustion phenotype. Gene co-expression analysis identified gene modules associated with asthma diagnosis, lung function, and biomarkers of type 2 inflammation were enriched in effector cells. These data identify adipose tissue dysfunction occurs in obesity-associated asthma and support adipose tissue as therapeutic target to address the enhanced asthma risk among those with obesity. NIH U01AI155299, P30DK020593, R01AI182159, K23HL159351, UL1RR024975-03, P30CA68485, P30EY08126, G20RR030956, 5UL1TR002243, KL2TR002245, P30AI110527, DK020593, American Heart Association 17SFRN33520017.

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