Karatepe, Kutay

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Karatepe, Kutay

Karatepe

Kutay

Karatepe, Kutay

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Role of Proteinase 3 in bone marrow hematopoiesis and neutrophil function
(2016-09-07) Karatepe, Kutay; Mizgerd, Joseph; Mitchell, James; Yuan, Zhi-Min; Chai, Li
The hematopoietic system requires finely-tuned regulatory mechanisms to supply the continuous demand of short-lived blood cells while maintaining a healthy hematopoietic stem cell compartment. Proteinase 3 (PR3), a member of neutrophil serine proteases, has a unique role in the regulation of hematopoiesis among its family members. PR3, which has been thought to be expressed exclusively in mature myeloid cells and myeloid progenitors, is expressed in hematopoietic stem cells. PR3 deletion expanded the hematopoietic stem and progenitor cell compartments. Absence of PR3 led to increased short-term regeneration potential, accompanied with a defect in production of lymphoid cells, particularly T cells. A more focused analysis led to identification of reduced cell death due to a defect in caspase 3 cleavage, but not proliferation, as the mechanism for elevated hematopoiesis seen in PR3 deficiency. PR3-deficient hematopoietic stem cells displayed exacerbated features associated with ageing. In spite of the previously proposed roles of PR3 in neutrophil function such as microbicidal activity, PR3 deficiency did not reveal a major defect in neutrophil functions except for IL1β secretion. Overall, this study identifies PR3 as a physiological regulator of hematopoietic stem cell compartment and function.