Neutrophil remodeling is associated with human meibomian gland dysfunction and enables IFN-γ- and PAD4-dependent gland obstruction in mice

Meibomian gland dysfunction (MGD), a disorder affecting the eyelid's modified sebaceous glands, is the primary cause of dry eye disease and ocular surface issues. The immune mechanisms behind gland obstruction have been unclear. A study of 66 patients with ocular surface inflammation employed meibography and spectral flow cytometry of tear washes, uncovering a disease-associated, remodeled neutrophil state linked to gland atrophy.

Single-cell transcriptomics in a mouse model of immune-mediated MGD unveiled a disease-associated neutrophil state with ocular surface enrichment, CD14 and ICAM-1 expression, heightened IFN-γ response, and inflammatory traits. Spatial transcriptomics pinpointed IFN-γ signaling and neutrophil migration to the periglandular region.

The remodeled neutrophils displayed PAD4-dependent histone citrullination; deleting Padi4 reduced NET-associated obstructive plugging, identifying PAD4-dependent NETotic activity as their disease-inducing result. Blocking IFN-γ signaling emulated Padi4 deficiency, but simultaneous inhibition of both pathways offered no added protection, suggesting that IFN-γ and PAD4 function as distinct essential inputs.

Remodeled neutrophils amassed under both scenarios, dissociating disease severity from cell count alone. These findings propose immune-mediated obstructive MGD as a mechanistic endotype driven by the IFN-γ- and PAD4-dependent effector output of a remodeled neutrophil state.