DNA binding to TLR9 expressed by red blood cells promotes innate immune activation and anemia. Sci Transl Med 2021; 13:eabj1008. PMID: 34669439. Erythrocytes are essential for oxygen delivery, but also have nongas exchanging immune functions. It was recently discovered that erythrocytes express toll-like receptor 9 (TLR9), which scavenges cell-free CpG-containing DNA (derived from bacteria or host mitochondria). However, how erythrocyte-dependent DNA binding contributes to inflammation during

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... fections remains unclear. TLR9 expression was found to be increased on the surface of erythrocytes in murine models of sepsis and in critically ill patients with sepsis, and to facilitate sequestration of CpG-containing DNA. TLR9-mediated DNA binding altered the morphology of erythrocytes due to changes in the cytoskeletal proteins spectrin and actin. Subsequent loss of the antiphagocytotic epitope of the CD47 protein, also expressed on the surface of erythrocytes, leads to accelerated phagocytosis of erythrocytes in the spleen accompanied by activation of macrophages with increased production of the proinflammatory cytokines interferon-γ and interleukin-6. Using an erythrocyte-specific TLR9 knockout mouse model, it was possible to show that both phagocytosis of CpG-tagged erythrocytes as well as CpG-induced inflammation were directly dependent on TLR9 expression. Erythrocyte-bound DNA was found to be higher in critically ill sepsis patients with anemia (less than or equal to 7 g/dl) as well as severely diseased (Apache score III) anemic (less than or equal to 9.6 g/dl) COVID-19 patients. (Article Selection: Michael Zaugg, M.D. Image: Getty Images.) Take home message: Erythrocytes function as immune sensors and alert the immune system to the presence of pathogens and tissue damage. This pathogen-sensing role comes at a cost, namely inflammation-induced anemia. The International Guidelines for the Management of Sepsis and Septic Shock are widely used since 2008 to guide sepsis treatment. The document updates its most recent iteration (2017). Clinical questions were structured in the Population, Intervention, Control, and Outcomes format and evaluated using the GRADE approach with the quality of evidence scored as high, moderate, low, or very low. Best practice statements are ungraded strong recommendations. A total of 93 recommendations are reported, addressing screening and initial resuscitation, infection, hemodynamics, ventilation, additional therapies, and goals of care and long-term outcomes. The majority of recommendations are based on weak evidence (58%). Selected highlights include downgrading the recommendation for 30 ml/kg IV crystalloid for initial resuscitation in patients with hypoperfusion or septic shock from a strong to a weak recommendation based on low quality of evidence. Also, recommending against use of quick sequential organ failure assessment as a sole screening tool. Antibiotic recommendations include delivering antimicrobials within 1 h of sepsis recognition with stratification of timing based on the likelihood of sepsis and presence of shock. For patients with possible sepsis without shock, rapid assessment of the likelihood of infection should be performed. Antimicrobials should be administered within 3 h from when sepsis was first recognized if suspicion persists.