Epigenetic rewiring of autophagy receptor hierarchy by beta-glucan training biases monocyte function toward pathogen clearance at the expense of mitochondrial quality control

Hypothesis

Beta-glucan–induced trained immunity reprograms the transcriptional hierarchy of selective autophagy receptors in monocytes, elevating antimicrobial receptors (NDP52, OPTN) while suppressing the multifunctional scaffold p62/SQSTM1. This shift redirects autophagic flux from mitophagy and protein‑aggregate clearance toward LC3‑associated phagocytosis of pathogens, thereby linking epigenetic training to a functional trade‑off that becomes detrimental with age.

Mechanistic premise

• Beta-glucan engages Dectin‑1/CLEC7A, triggering H3K4me3 deposition at promoters of autophagy‑receptor genes [3].
• We propose that this epigenetic mark preferentially enhances transcription of NDP52 and OPTN, which are enriched in pathogen‑associated microdomains [1], whereas p62 transcription is restrained through concurrent H3K27me3 enrichment or reduced promoter accessibility.
• Altered receptor stoichiometry changes the competition for LC3 and ubiquitin cargos: NDP52/OPTN dominate phagosomal membranes, driving LC3‑associated phagocytosis (LAP) and inflammasome priming [2]; p62‑dependent mitophagy and NF‑κB attenuation wane [4]
• In young monocytes the trade‑off is balanced by high basal autophagic flux; with aging, global autophagy declines and the p62‑deficit cannot be compensated, leading to accumulation of damaged mitochondria, heightened mtROS, and chronic NLRP3 inflammasome activation.

Testable predictions

1. Young human monocytes treated with β‑glucan will show increased NDP52 and OPTN mRNA/protein (qPCR, flow) and decreased p62 levels after 24 h, accompanied by gain of H3K4me3 at NDP52/OPTN promoters (ChIP‑qPCR).
2. Mitochondrial autophagy flux, measured by mt‑Keima or LC3‑II turnover in the presence of lysosomal inhibitors, will be significantly lower in β‑glucan‑treated young monocytes compared with untreated cells, while LAP of opsonized yeast particles will be elevated.
3. In monocytes from donors >65 years, baseline p62 expression will already be reduced; β‑glucan treatment will not further lower p62 but will exacerbate the deficit in mitophagy, resulting in higher mtROS and increased caspase‑1 cleavage/IL‑1β release.
4. Restoring p62 via lentiviral overexpression in aged, β‑glucan‑treated monocytes will rescue mitophagy flux, diminish mtROS, and blunt inflammasome activation without affecting LAP of pathogens.

Falsification If β‑glucan fails to modify the receptor ratio (no change in NDP52/OPTN versus p62) or if manipulating p62 does not influence mitochondrial quality or inflammasome output as predicted, the hypothesis would be refuted.

This framework links epigenetic rewiring of a selective‑autophagy hierarchy to a mechanistic explanation for how trained immunity can precipitate age‑related myeloid dysfunction.