Impaired IL-10 Receptor Signaling Leads to Inflammation Induced Exhaustion in Hematopoietic Stem Cells

Chronic-inflammation compromises normal hematopoiesis, and interleukin-10 (IL-10) signaling is essential for restraining inflammatory responses. When inflammation persists, hematopoietic stem cells (HSCs) undergo proliferative exhaustion with loss of fitness and regenerative capacity. We previously showed that in JAK2V617F myeloproliferative neoplasm (MPN) primary monocytes exhibit impaired IL-10 signaling. Because clonal hematopoiesis is a hallmark of exhaustion, we hypothesize that impaired IL-10 signaling confers a selective advantage to clonal hematopoiesis by promoting inflammation-induced exhaustion in nonmalignant cells. We used an IL-10R blocking antibody in murine models with repeated exposure to lipopolysaccharide (LPS), an inflammatory stimulus, this showed IL-10R blockade exacerbated exhaustion phenotypes, increasing proliferation, myeloid skewing, and reduced HSC fitness relative to controls. In JAK2V617F murine models, JAK2V617F-expressing cells were not impaired by inflammatory exposure in the presence of IL-10R blockade, which in turn aggravated MPN-like phenotypes and clonal expansion. Taken together, these findings indicate that defective IL-10 receptor signaling prolongs inflammatory responses, accelerates exhaustion phenotypes, and reduces the competitiveness of normal hematopoietic clones in the context of hematologic malignancy.