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In vivo reprogramming of pathogenic lung TNFR2⁺ cDC2s by IFNβ inhibits HDM-induced asthma.

ABSTRACT: Asthma is a common inflammatory lung disease with no known cure. Previously, we uncovered a lung TNFR2⁺ conventional DC2 subset (cDC2s) that induces regulatory T cells (T_regs) maintaining lung tolerance at steady state but promotes T_H2 response during house dust mite (HDM)-induced asthma. Lung IFNβ is essential for TNFR2⁺ cDC2s-mediated lung tolerance. Here, we showed that exogenous IFNβ reprogrammed T_H2-promoting pathogenic TNFR2⁺ cDC2s back to tolerogenic DCs, alleviating eosinophilic asthma and preventing asthma exacerbation. Mechanistically, inhaled IFNβ, not IFNα, activated ERK2 signaling in pathogenic lung TNFR2⁺ cDC2s, leading to enhanced fatty acid oxidation (FAO) and lung T_reg induction. Last, human IFNβ reprogrammed pathogenic human lung TNFR2⁺ cDC2s from patients with emphysema ex vivo. Thus, we identified an IFNβ-specific ERK2-FAO pathway that might be harnessed for DC therapy.

SUBMITTER: Mansouri S

PROVIDER: S-EPMC8323989 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rationale: Monocytes play critical roles in the pathogenesis of arthritis by contributing to the inflammatory response and bone erosion. Among genes involved in regulating monocyte functions, miR-146a negatively regulates the inflammatory response and osteoclast differentiation of monocytes. It is also the only miRNA reported to differentially regulate the cytokine response of the two classical Ly6Chigh and non-classical Ly6Clow monocyte subsets upon bacterial challenge. Although miR-146a is overexpressed in many tissues of arthritic patients, its specific role in monocyte subsets under arthritic conditions remains to be explored. Methods: We analyzed the monocyte subsets during collagen-induced arthritis (CIA) development by flow cytometry. We quantified the expression of miR-146a in classical and non-classical monocytes sorted from healthy and CIA mice, as well as patients with rheumatoid arthritis (RA). We monitored arthritis features in miR-146a-/- mice and assessed in vivo the therapeutic potential of miR-146a mimics delivery to Ly6Chigh monocytes. We performed transcriptomic and pathway enrichment analyses on both monocyte subsets sorted from wild type and miR-146a-/- mice. Results: We showed that the expression of miR-146a is reduced in the Ly6Chigh subset of CIA mice and in the analogous monocyte subset (CD14+CD16-) in humans with RA as compared with healthy controls. The ablation of miR-146a in mice worsened arthritis severity, increased osteoclast differentiation in vitro and bone erosion in vivo. In vivo delivery of miR-146a to Ly6Chigh monocytes, and not to Ly6Clow monocytes, rescues bone erosion in miR-146a-/- arthritic mice and reduces osteoclast differentiation and pathogenic bone erosion in CIA joints of miR-146a+/+ mice, with no effect on inflammation. Silencing of the non-canonical NF-κB family member RelB in miR-146a-/- Ly6Chigh monocytes uncovers a role for miR-146a as a key regulator of the differentiation of Ly6Chigh, and not Ly6Clow, monocytes into osteoclasts under arthritic conditions. Conclusion: Our results show that classical monocytes play a critical role in arthritis bone erosion. They demonstrate the theranostics potential of manipulating miR-146a expression in Ly6Chigh monocytes to prevent joint destruction while sparing inflammation in arthritis.

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In vivo reprogramming of pathogenic lung TNFR2+ cDC2s by IFNβ inhibits HDM-induced asthma.

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In vivo reprogramming of pathogenic lung TNFR2⁺ cDC2s by IFNβ inhibits HDM-induced asthma.