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Monocyte procoagulant responses to anthrax peptidoglycan are reinforced by proinflammatory cytokine signaling.
Blood Adv 2019; 3(16):2436-2447BA

Abstract

Disseminated intravascular coagulation is a frequent manifestation during bacterial infections and is associated with negative clinical outcomes. Imbalanced expression and activity of intravascular tissue factor (TF) is central to the development of infection-associated coagulopathies. Recently, we showed that anthrax peptidoglycan (PGN) induces disseminated intravascular coagulation in a nonhuman primate model of anthrax sepsis. We hypothesized that immune recognition of PGN by monocytes is critical for procoagulant responses to PGN and investigated whether and how PGN induces TF expression in primary human monocytes. We found that PGN induced monocyte TF expression in a large cohort of healthy volunteers similar to lipopolysaccharide stimulation. Both immune and procoagulant responses to PGN involve intracellular recognition after PGN internalization, as well as surface signaling through immune Fcγ receptors (FcγRs). In line with our hypothesis, blocking immune receptor function, both signaling and FcγR-mediated phagocytosis, significantly reduced but did not abolish PGN-induced monocyte TF expression, indicating that FcγR-independent internalization contributes to intracellular recognition of PGN. Conversely, when intracellular PGN recognition is abolished, TF expression was sensitive to inhibitors of FcγR signaling, indicating that surface engagement of monocyte immune receptors can promote TF expression. The primary procoagulant responses to PGN were further amplified by proinflammatory cytokines through paracrine and autocrine signaling. Despite intersubject variability in the study cohort, dual neutralization of tumor necrosis factor-α and interleukin-1β provided the most robust inhibition of the procoagulant amplification loop and may prove useful for reducing coagulopathies in gram-positive sepsis.

Authors+Show Affiliations

Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK.Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK.Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK.Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK.Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31416821

Citation

Popescu, Narcis Ioan, et al. "Monocyte Procoagulant Responses to Anthrax Peptidoglycan Are Reinforced By Proinflammatory Cytokine Signaling." Blood Advances, vol. 3, no. 16, 2019, pp. 2436-2447.
Popescu NI, Girton A, Burgett T, et al. Monocyte procoagulant responses to anthrax peptidoglycan are reinforced by proinflammatory cytokine signaling. Blood Adv. 2019;3(16):2436-2447.
Popescu, N. I., Girton, A., Burgett, T., Lovelady, K., & Coggeshall, K. M. (2019). Monocyte procoagulant responses to anthrax peptidoglycan are reinforced by proinflammatory cytokine signaling. Blood Advances, 3(16), pp. 2436-2447. doi:10.1182/bloodadvances.2019000513.
Popescu NI, et al. Monocyte Procoagulant Responses to Anthrax Peptidoglycan Are Reinforced By Proinflammatory Cytokine Signaling. Blood Adv. 2019 Aug 27;3(16):2436-2447. PubMed PMID: 31416821.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Monocyte procoagulant responses to anthrax peptidoglycan are reinforced by proinflammatory cytokine signaling. AU - Popescu,Narcis Ioan, AU - Girton,Alanson, AU - Burgett,Tarea, AU - Lovelady,Kessa, AU - Coggeshall,K Mark, PY - 2019/02/05/received PY - 2019/06/17/accepted PY - 2019/8/17/entrez PY - 2019/8/17/pubmed PY - 2019/8/17/medline SP - 2436 EP - 2447 JF - Blood advances JO - Blood Adv VL - 3 IS - 16 N2 - Disseminated intravascular coagulation is a frequent manifestation during bacterial infections and is associated with negative clinical outcomes. Imbalanced expression and activity of intravascular tissue factor (TF) is central to the development of infection-associated coagulopathies. Recently, we showed that anthrax peptidoglycan (PGN) induces disseminated intravascular coagulation in a nonhuman primate model of anthrax sepsis. We hypothesized that immune recognition of PGN by monocytes is critical for procoagulant responses to PGN and investigated whether and how PGN induces TF expression in primary human monocytes. We found that PGN induced monocyte TF expression in a large cohort of healthy volunteers similar to lipopolysaccharide stimulation. Both immune and procoagulant responses to PGN involve intracellular recognition after PGN internalization, as well as surface signaling through immune Fcγ receptors (FcγRs). In line with our hypothesis, blocking immune receptor function, both signaling and FcγR-mediated phagocytosis, significantly reduced but did not abolish PGN-induced monocyte TF expression, indicating that FcγR-independent internalization contributes to intracellular recognition of PGN. Conversely, when intracellular PGN recognition is abolished, TF expression was sensitive to inhibitors of FcγR signaling, indicating that surface engagement of monocyte immune receptors can promote TF expression. The primary procoagulant responses to PGN were further amplified by proinflammatory cytokines through paracrine and autocrine signaling. Despite intersubject variability in the study cohort, dual neutralization of tumor necrosis factor-α and interleukin-1β provided the most robust inhibition of the procoagulant amplification loop and may prove useful for reducing coagulopathies in gram-positive sepsis. SN - 2473-9537 UR - https://www.unboundmedicine.com/medline/citation/31416821/Monocyte_procoagulant_responses_to_anthrax_peptidoglycan_are_reinforced_by_proinflammatory_cytokine_signaling L2 - http://www.bloodadvances.org/cgi/pmidlookup?view=long&pmid=31416821 DB - PRIME DP - Unbound Medicine ER -