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Exosomal Transfer of Mitochondria Reprograms T Helper Cell Function In Chronic Airway Inflammation

ABSTRACT: Cell-to-cell communication in complex multicellular organisms is mediated by soluble factors and extracellular vesicles that include exosomes. Myeloid-derived regulatory cells (MDRCs) are regulators of CD4+ T cell responses in asthma. Here, we demonstrate that airway MDRC-derived exosomes from asthmatics mediate T cell receptor engagement and mitochondrial transfer that promote antigen-specific activation and polarization of Th17 and Th2 cells, drivers of chronic airway inflammation in asthma. Exosomal mitochondria are internalized by CD4+ T cells predominantly by membrane fusion, although their activation is internalization-independent. Additionally, blocking mitochondrial oxidant signaling in MDRC-derived exosomes mitigates T cell activation. In asthmatics, a Drp1-dependent mitochondrial fission process in pro-inflammatory MDRCs generates exosomal mitochondria. Importantly, internalized exosomal mitochondria co-localize with polarized cytoskeleton and mitochondrial networks suggesting a role in organization of the immune synapse in recipient T cells. These results indicate an unrecognized role for mitochondrial fission and exosomal transfer in immunological cross-talk in chronic airway inflammation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144813 | GEO | 2026/03/02

REPOSITORIES: GEO

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Project description:Background: The first step in SARS-CoV-2 infection is binding of the virus to angiotensin converting enzyme 2 (ACE2) on the airway epithelium. Asthma affects over 300 million people world-wide, many of whom may encounter SARS-CoV-2. Epidemiologic data suggests that asthmatics who get infected may be at increased risk of more severe disease. Our objective was to assess whether maintenance inhaled corticosteroids (ICS), a major treatment for asthma, is associated with airway ACE2 expression in asthmatics. Methods: Large airway epithelium (LAE) of asthmatics treated with maintenance ICS (ICS+), asthmatics not treated with ICS (ICS-), and healthy controls (controls) was analyzed for expression of ACE2 and other coronavirus infection-related genes using microarrays. Results: AsResults: As a group, there was no difference in LAE ACE2 expression in all asthmatics vs controls. In contrast, subgroup analysis demonstrated that LAE ACE2 expression was higher in asthmatics ICS+ compared to ICS‾ and ACE2 expression was higher in male ICS+ compared to female ICS+ and ICS‾ of either sex. ACE2 expression did not correlate with serum IgE, absolute eosinophil level, or change in FEV1 in response to bronchodilators in either ICS- or ICS+. Conclusion: Airway ACE2 expression is increased in asthmatics on long-term treatment with ICS, an observation that should be taken into consideration when assessing the use of inhaled corticosteroids during the pandemic. a group, there was no difference in LAE ACE2 expression in all asthmatics vs controls. In contrast, subgroup analysis demonstrated that LAE ACE2 expression was higher in asthmatics ICS+ compared to ICS‾ and ACE2 expression was higher in male ICS+ compared to female ICS+ and ICS‾ of either sex. ACE2 expression did not correlate with serum IgE, absolute eosinophil level, or change in FEV1 in response to bronchodilators in either ICS- or ICS+. Conclusion: Airway ACE2 expression is increased in asthmatics on long-term treatment with ICS, an observation that should be taken into consideration when assessing the use of inhaled corticosteroids during the pandemic.

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Exosomal Transfer of Mitochondria Reprograms T Helper Cell Function In Chronic Airway Inflammation

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