Immune landscape and the key role of APOE+ monocytes of lupus nephritis under the single-cell and spatial transcriptional vista.

Background: Lupus nephritis (LN) is among the most common complication of systemic lupus erythematosus (SLE) with high mortality and morbidity. The analysis of LN kidney's local immune response through single-cell and spatial transcriptome enables the study of potential therapeutic targets.

Methods: By single cell sequencing and spatial transcriptome, we profile cells from LN kidney and normal kidney tissues to characterize cellular composition and elucidate the potential upstream monocyte/macrophage (Mono/MΦ) initiating the auto-immune response. After the high-throughput synergy screening, we performed the immunofluorescence to identify the specific cells in LN patients. The function experiments were finished by flow cytometry and Elisa.

Results: By immunofluorescence and spatial transcriptome, we identified differential subsets of Mono/MΦ and demonstrated that they exhibit temporal expression of TIMP1, IL1B, SPP1 and APOE. With the function experiments, we found that the APOE+ Mono may be compensatorily increased in LN, and the capacity of antigen presenting was decreased with the overexpression of APOE. Furthermore, how do the LN-specific Mono/MΦ transport in and out the glomerulus to active the local immune response remains unclear. Our results showed that lymphangiogenesis occurred in LN kidneys but not in normal kidneys, suggesting the presence of a new lymphatic vessel may serve as a 'green channel' for LN-specific Mono/MΦ.

Conclusions: In LN, APOE+ Mono are compensatorily elevated, with decreased antigen presenting ability and reduced secretion of interferons. The lymphangiogenesis in LN prompts the trafficking of Mono/MΦ in LN kidney.