Bone marrow neutropoiesis bias underlies inflammatory comorbidities [multiomics]

Local chronic inflammation exacerbates the prevalence and severity of associated distal organ comorbidities, causing catastrophic consequences for patients. However, the underlying mechanisms remain unclear. Here, we found that periodontitis increased the circulating pro-inflammatory neutrophils, which could be easily recruited to rheumatoid arthritis (RA) joints and aggravated articular destruction. Single-cell multiomics sequencing has revealed that periodontitis induces transcriptomic and epigenomic rewiring of hematopoietic stem and progenitor cells (HSPCs), which display skewed differentiation toward the neutrophil lineage, resulting in an increase in pro-inflammatory neutrophils. We further identified that periodontitis-elevated type I interferons are responsible for guiding the continuous neutropoiesis bias in the bone marrow. Resolution of periodontitis can reverse the differentiation bias of HSPCs and alleviate the progression of RA. This study indicated that neutropoiesis bias induces the progression of inflammatory comorbidities and emphasizes the necessity of controlling local chronic inflammation in the management of inflammatory comorbidities.