11/23/2023 0 Comments Statplus 20093 Thus, the ability of the BM to respond to infections by expanding the progenitors and producing differentiated cells capable of destroying the microbial pathogens, while preserving an intact stem cell pool, is a critical feature of host defense that translates into the difference between resolving an infection or succumbing to it. Due to their short life span, neutrophils have to be supplied continuously during infection by expansion of myeloid progenitors in the bone marrow (BM). 2 During infection, neutrophils rapidly migrate to the site of inflammation where they initiate their antimicrobial activity. A key component of the host innate response to bacterial pathogens is the neutrophil. 1 The systemic inflammation underlying sepsis results initially from the “failure” of the host innate immune system to control invasive pathogens. 1 The severe complications present during sepsis are largely due to the excessive release of cytokines that lead progressively to endothelial dysfunction, coagulation cascade activation, microvascular injury, and, in many cases, multiple organ failure. Sepsis is a complex clinical syndrome, a devastating consequence of bacterial infection that frequently causes severe organ dysfunction, and is the leading cause of death in noncoronary intensive care units. Our results establish a previously unrecognized link between HSC regulation and host response in severe sepsis and demonstrate a novel role for TLR4. Pseudomonas's lipopolysaccharide was necessary and sufficient to induce myelosuppresion and required intact TLR4 signaling. Delayed myeloid-neutrophil differentiation was further mapped using a lysozyme–green fluorescent protein (GFP) reporter mouse. ![]() “Septic” HSCs were significantly impaired in competitive repopulation assays and defective in generating common myeloid progenitors and granulocyte-monocyte progenitors, resulting in lower rates of myeloid differentiation in vitro and in vivo. Using a sepsis murine model, we found that the human opportunistic bacterial pathogen Pseudomonas aeruginosa caused neutrophil depletion and expansion of the HSC pool in the bone marrow. Here, we show that neutropenia is caused in part by apoptosis and is sustained by a block of hematopoietic stem cell (HSC) differentiation. Despite the central role of neutrophils in innate immunity, the mechanisms causing neutropenia during sepsis remain elusive. High mortality rates in sepsis are frequently associated with neutropenia. ![]() Severe sepsis is one of the leading causes of death worldwide.
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