Abstract
Production of innate and adaptive immune cells from hematopoietic stem cells, and maturation of T lymphocytes are effective immune responses to fight severe microbial infection. In sepsis, this emergency myelopoiesis is damaged, leading to failure of bacterial clearance, and excessive stress-induced steroids cause immature T-lymphocyte apoptosis in thymus. We recently found that Cl-amidine, a peptidylarginine deiminase (PAD) inhibitor, improves survival in a mouse model of cecal ligation and puncture (CLP)-induced septic shock. In the present study we investigated how Cl-amidine promotes survival, focusing on protective effects of Cl-amidine on immune response. We confirmed survival-improving effect of Cl-amidine and are the first to explore the role of Cl-amidine in immune response. CLP caused bone marrow (BM) and thymus atrophy, decreased innate immune cells in BM. CLP increased levels of cytokines (IL-1β, IL-6, and TNF-α) and bacteria load in blood/liver. In primary splenocyte culture, lipopolysaccharide increased TNF-α production. In contrast, Cl-amidine attenuated these CLP and lipopolysaccharide-induced alterations. Moreover, Cl-amidine increased circulating monocytes. Collectively, our results demonstrate Cl-amidine plays protective roles by significantly decreasing BM and thymus atrophy, restoring innate immune cells in BM, increasing blood monocytes and blood/liver bacteria clearance, and attenuating pro-inflammatory cytokine production in a murine model of lethal sepsis.
Highlights
40 mg/kg of Cl-amidine dissolved in DMSO or vehicle DMSO 1 h after CLP
DMSO was injected into normal mice (DMSO group) and mice that were operated but not subjected to CLP (Sham +DMSO group)
CLP-subjected animals treated with Protein-arginine deiminase (PAD) inhibitor Cl-amidine had higher long-term survival rate compared to CLP +DMSO group (50% versus 0% survival)
Summary
40 mg/kg of Cl-amidine dissolved in DMSO or vehicle DMSO 1 h after CLP. DMSO was injected into normal mice (DMSO group) and mice that were operated but not subjected to CLP (Sham +DMSO group). CLP-subjected animals treated with PAD inhibitor Cl-amidine had higher long-term survival rate compared to CLP +DMSO group (50% versus 0% survival). The current study aimed to investigate effects of Cl-amidine on survival outcomes, and explore effects of Cl-amidine on atrophy of immune organs, composition of immune cells in bone marrow and blood, bacteria clearance in liver and blood, and inflammatory responses
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