Innate immune responses to trauma.

Trauma can affect any individual at any location and at any time over a lifespan. The disruption of macrobarriers and microbarriers induces instant activation of innate immunity. The subsequent complex response, designed to limit further damage and induce healing, also represents a major driver of complications and fatal outcome after injury. This Review aims to provide basic concepts about the posttraumatic response and is focused on the interactive events of innate immunity at frequent sites of injury: the endothelium at large, and sites within the lungs, inside and outside the brain and at the gut barrier.

Understanding Immunosuppression after Sepsis.

Following a severe primary infection or trauma, the risk of developing pneumonia increases due to acquired immune defects collectively known as sepsis-induced immunosuppression. In this issue of Immunity, Roquilly et al. (2017) show that dendritic cells and macrophages developing in the lung after the resolution of a severe infection acquire tolerogenic properties that contribute to persistent immunosuppression and susceptibility to secondary infections.

Externalized histones fuel pulmonary fibrosis via a platelet-macrophage circuit of TGFß1 and IL-27.

Externalized histones erupt from the nucleus as extracellular traps, are associated with several acute and chronic lung disorders, but their implications in the molecular pathogenesis of interstitial lung disease are incompletely defined. To investigate the role and molecular mechanisms of externalized histones within the immunologic networks of pulmonary fibrosis, we studied externalized histones in human and animal bronchoalveolar lavage (BAL) samples of lung fibrosis. Neutralizing anti-histone antibodies were administered in bleomycin-induced fibrosis of C57BL/6 J mice, and subsequent studies used conditional/constitutive knockout mouse strains for TGFß and IL-27 signaling along with isolated platelets and cultured macrophages. We found that externalized histones (citH3) were significantly (P < 0.01) increased in cell-free BAL fluids of patients with idiopathic pulmonary fibrosis (IPF; n = 29) as compared to healthy controls (n = 10). The pulmonary sources of externalized histones were Ly6G+CD11b+ neutrophils and nonhematopoietic cells after bleomycin in mice. Neutralizing monoclonal anti-histone H2A/H4 antibodies reduced the pulmonary collagen accumulation and hydroxyproline concentration. Histones activated platelets to release TGFß1, which signaled through the TGFbRI/TGFbRII receptor complex on LysM+ cells to antagonize macrophage-derived IL-27 production. TGFß1 evoked multiple downstream mechanisms in macrophages, including p38 MAPK, tristetraprolin, IL-10, and binding of SMAD3 to the IL-27 promotor regions. IL-27RA-deficient mice displayed more severe collagen depositions suggesting that intact IL-27 signaling limits fibrosis. In conclusion, externalized histones inactivate a safety switch of antifibrotic, macrophage-derived IL-27 by boosting platelet-derived TGFß1. Externalized histones are accessible to neutralizing antibodies for improving the severity of experimental pulmonary fibrosis.

Standard -20 °C freezer storage protocols may cause substantial plasma renin cryoactivation.

OBJECTIVES: To assess the appropriate preanalytical process for storage of plasma for renin concentration analysis. This study was initiated due to the wide variation in preanalytical handling of samples observed within our network, particularly with respect to freezing for longer term storage. METHODS: Pooled plasma from patient samples was analysed immediately post separation for renin concentration (n=30, concentration 4.0-204 mIU/L). Aliquots from these samples were frozen in a -20 °C freezer and then analysed, with the renin concentration compared to the respective baseline concentration. Comparisons were also made to: aliquots snap frozen using a dry ice/acetone bath, aliquots stored at room temperature, and aliquots stored at 4 °C. Subsequent experiments investigated the potential sources of cryoactivation observed in these initial studies. RESULTS: Substantial and highly variable cryoactivation was observed in samples frozen using a -20 °C freezer, with renin concentration increasing over 300% from baseline in some samples (median 21.3%). This cryoactivation could be prevented by snap freezing samples. Subsequent experiments determined that long term storage in a -20 °C freezer could prevent cryoactivation provided samples were initially frozen rapidly in a -70 °C freezer. Rapid defrosting of samples was not required to prevent cryoactivation. CONCLUSIONS: Standard -20 °C freezers may not be appropriate for freezing samples for renin analysis. Laboratories should consider snap freezing their samples using a -70 °C freezer or similar to avoid cryoactivation of renin.

"Older People Want to Be in Their Own Homes": A Service Evaluation of Patient and Carer Feedback after Pathfinder Responded to Their Emergency Calls.

OBJECTIVE: Older people experience high rates of adverse outcomes following emergency department (ED) presentation. There is growing evidence to support alternative care pathways for certain types of emergency medical services (EMS) calls. Pathfinder is one such service and targets patients aged 65 years and over, whose presenting issues can be safely managed at home by immediate paramedic, occupational therapy, and/or physiotherapy interventions. The aim of this service evaluation was to understand how older people feel about being treated at home as a result of EMS calls and to understand their experiences of the Pathfinder service. METHODS: This was a thematic analysis of open-ended responses recorded from telephone interviews during routine service evaluation with service users (patients or their next-of-kin). RESULTS: Of 573 service users, telephone interviews were conducted with 429 (75%). Five primary themes were identified: (1) professionalism of the multidisciplinary clinical team; (2) "the right service, in the right place, at the right time"; (3) role of Pathfinder in "getting the ball rolling"; (4) lasting effects of the experience on the patient and his or her next-of-kin; (5) value of skilled communication with the older person. CONCLUSION: Older people and their next-of-kin voiced a clear preference for hospital avoidance, and strongly valued the opportunity to be treated in their homes at the time of an EMS call rather than default conveyance to the ED. They appreciated the importance of a skilled multidisciplinary team with a follow-up service that effectively positions itself between the acute hospital and community services.

The bipolar role of miR-466l in inflammation.

Special proresolving mediators (SPMs) limit the intensity of inflammation; however, their regulation is poorly understood. In this issue of Immunity, Li et al. (2013) describe bipolar roles for miR-466l in the promotion of inflammation and the induction of SPMs.

Requirement of Complement C6 for Intact Innate Immune Responses in Mice.

Over the first days of polymicrobial sepsis, there is robust activation of the innate immune system, causing the appearance of proinflammatory cytokines and chemokines, along with the appearance of extracellular histones, which are highly proinflammatory and prothrombotic. In the current study, we studied different innate immune responses in mice with knockout (KO) of complement protein 6 (C6). Polymorphonuclear neutrophils (PMNs) from these KO mice had defective innate immune responses, including defective expression of surface adhesion molecules, generation of superoxide anion, and appearance of reactive oxygen species and histone release after activation of PMNs, along with defective phagocytosis. In addition, in C6-/- mice, the NLRP3 inflammasome was defective both in PMNs and in macrophages. When these KO mice were subjected to polymicrobial sepsis, their survival was improved, associated with reduced levels in the plasma of proinflammatory cytokines and chemokines and lower levels of histones in plasma. In addition, sepsis-induced cardiac dysfunction was attenuated in these KO mice. In a model of acute lung injury induced by LPS, C6-/- mice showed reduced PMN buildup and less lung epithelial/endothelial cell dysfunction (edema and hemorrhage). These data indicate that C6-/- mice have reduced innate immune responses that result in less organ injury and improved survival after polymicrobial sepsis.

Optimizing Huddle Engagement Through Leadership and Problem Solving Within Primary Care: Results from a Cluster-Randomized Trial.

BACKGROUND: Leaders play a crucial role in implementing and sustaining changes in clinical practice, yet there is limited evidence on the strategies to engage them in team problem solving and communication. OBJECTIVE: Examine the impact of an intervention focused on facilitating leadership during daily huddles on optimizing team-based care and improving outcomes. DESIGN: Cluster-randomized trial using intention-to-treat analysis to measure the effects of the intervention (n = 13 teams) compared with routine practice (n = 16 teams). PARTICIPANTS: Twenty-nine primary care clinics affiliated with a large integrated health system in the upper Midwest; representing differing practice types and geographic settings. INTERVENTION: Full-day leadership training retreat for team leaders to facilitate of care team huddles. Biweekly coaching calls and two site visits with an assigned coach. MAIN MEASURES: Primary outcomes of team development and function were collected, pre- and post-intervention using surveys. Patient satisfaction and quality outcomes were compared pre- and post-intervention as secondary outcomes. Leadership engagement and adherence to the intervention were also assessed. KEY RESULTS: A total of 279 pre-intervention and 272 post-intervention surveys were completed. We found no impact on team development (- 0.98, 95% CI (- 3.18, 1.22)), improved team credibility (0.18, 95% CI (0.00, 0.35)), but worse psychological safety (- 0.19, 95% CI (- 0.38, 0.00)). No differences were observed in patient satisfaction; however, results were mixed among quality outcomes. Post hoc analysis within the intervention group showed higher adherence to the intervention was associated with improvement in team coordination (0.47, 95% CI (0.18, 0.76)), credibility (0.28, 95% CI (0.02, 0.53)), team learning (0.42, 95% CI (0.10, 0.74)), and knowledge creation (0.74, 95% CI (0.35, 1.13)) compared to teams that were less engaged. CONCLUSIONS: Results of this evaluation showed that leadership training and facilitation were not associated with better team functioning. Additional components to the intervention tested may be necessary to enhance team functioning. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT03062670. Registration Date: February 23, 2017. URL: https://clinicaltrials.gov/ct2/show/NCT03062670.

GM-CSF Administration Improves Defects in Innate Immunity and Sepsis Survival in Obese Diabetic Mice.

Sepsis is the leading cause of death in the intensive care unit with an overall mortality rate of 20%. Individuals who are obese and have type 2 diabetes have increased recurrent, chronic, nosocomial infections that worsen the long-term morbidity and mortality from sepsis. Additionally, animal models of sepsis have shown that obese, diabetic mice have lower survival rates compared with nondiabetic mice. Neutrophils are essential for eradication of bacteria, prevention of infectious complications, and sepsis survival. In diabetic states, there is a reduction in neutrophil chemotaxis, phagocytosis, and reactive oxygen species (ROS) generation; however, few studies have investigated the extent to which these deficits compromise infection eradication and mortality. Using a cecal ligation and puncture model of sepsis in lean and in diet-induced obese mice, we demonstrate that obese diabetic mice have decreased "emergency hematopoiesis" after an acute infection. Additionally, both neutrophils and monocytes in obese, diabetic mice have functional defects, with decreased phagocytic ability and a decreased capacity to generate ROS. Neutrophils isolated from obese diabetic mice have decreased transcripts of Axl and Mertk, which partially explains the phagocytic dysfunction. Furthermore, we found that exogenous GM-CSF administration improves sepsis survival through enhanced neutrophil and monocytes phagocytosis and ROS generation abilities in obese, diabetic mice with sepsis.

Is Pathfinder a safe alternative to the emergency department for older patients? An observational analysis.

BACKGROUND: many patients brought to emergency departments (EDs) following an emergency medical services (EMS) call have non-urgent needs that could be treated elsewhere. Older people are particularly vulnerable to adverse events while attending the ED. Alternative care pathway models can reduce ED crowding and improve outcomes. Internationally, there is no consensus on which model is recommended. AIM: the aim of this study is to investigate the impact of the Pathfinder model on ED conveyance rates and patient safety. METHODS: the Pathfinder service is a collaboration between the National Ambulance Service and Beaumont Hospital Occupational Therapy and Physiotherapy Departments. It is supported by the Government of Ireland's Sláintecare Integration fund. This is a retrospective cohort study of the Pathfinder service over a 5-month period. RESULTS: one-hundred and seventy-eight patients were responded to by the Pathfinder 'Rapid Response Team'. Average age was 79.6 years (standard deviation 7.6), median clinical frailty score was 6 (interquartile range: 5-6). Sixty-four percent remained at home following initial review. None re-presented to the ED within 24 hours, and 10% re-presented within 7 days. The majority (67%) of patients required follow-up by the Pathfinder 'Follow-Up Team' and/or another community-based service. Feedback demonstrates 99% patient satisfaction with the service. CONCLUSION: the Pathfinder service is a safe alternative to ED conveyance for older people following an EMS call. It is the first model of this kind to be evaluated in Ireland. The overwhelmingly positive feedback confirms that older people want this service. This model could expand, with local adaptation, nationally and internationally.

A Structural Equation Model to Decipher Relationships among Water, Sanitation, and Health in Colonias-Type Unincorporated Communities.

The colonias along the United States-Mexico border are generally self-built neighborhoods of low-income families that lack basic infrastructure. While some government assistance has provided roads and electricity, water and wastewater services are still lacking in many colonias. This research is the first to collect a comprehensive dataset on water, sanitation, health, and living conditions in these unincorporated neighborhoods through collection of water samples and surveys; 114 households in 23 colonias across three geographically diverse Texas counties are studied. Water quality is assessed via traditional microbial indicators, chlorine, and arsenic. This complex dataset requires an advanced statistical tool to disentangle relationships among diverse factors. Structural equation modeling is utilized to identify relationships among surveyed and measured variables. The model reveals that colonias residents with well/hauled water accurately predict their water quality, while those with treated+piped water tend to think that their water is worse than it actually is. Dwelling quality and connection to sanitary sewers influence perceived health risks and household health, respectively. Furthermore, these communities have an overwhelming need and desire for point-of-use water treatment. This model can inform decision making and may be adapted to probe other questions and social dynamics for water and sanitation in unincorporated communities elsewhere.

The immune system's role in sepsis progression, resolution, and long-term outcome.

Sepsis occurs when an infection exceeds local tissue containment and induces a series of dysregulated physiologic responses that result in organ dysfunction. A subset of patients with sepsis progress to septic shock, defined by profound circulatory, cellular, and metabolic abnormalities, and associated with a greater mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the complex interplay between the initial inflammatory and later anti-inflammatory responses. With advances in intensive care medicine and goal-directed interventions, early 30-day sepsis mortality has diminished, only to steadily escalate long after "recovery" from acute events. As so many sepsis survivors succumb later to persistent, recurrent, nosocomial, and secondary infections, many investigators have turned their attention to the long-term sepsis-induced alterations in cellular immune function. Sepsis clearly alters the innate and adaptive immune responses for sustained periods of time after clinical recovery, with immune suppression, chronic inflammation, and persistence of bacterial representing such alterations. Understanding that sepsis-associated immune cell defects correlate with long-term mortality, more investigations have centered on the potential for immune modulatory therapy to improve long-term patient outcomes. These efforts are focused on more clearly defining and effectively reversing the persistent immune cell dysfunction associated with long-term sepsis mortality.

Apalutamide Absorption, Metabolism, and Excretion in Healthy Men, and Enzyme Reaction in Human Hepatocytes.

In this phase 1 study, the absolute bioavailability and absorption, metabolism, and excretion (AME) of apalutamide, a competitive inhibitor of the androgen receptor, were evaluated in 12 healthy men. Subjects received 240 mg of apalutamide orally plus a 15-minute intravenous infusion of 100 µg of apalutamide containing 9.25 kBq (250 nCi) of 14C-apalutamide (2 hours postdose) for absolute bioavailability assessment or plus one 400-µg capsule containing 37 kBq (1000 nCi) of 14C-apalutamide for AME assessment. Content of 14C and metabolite profiling for whole blood, plasma, urine, feces, and expired air samples were analyzed using accelerator mass spectrometry. Apalutamide absolute oral bioavailability was ≈100%. After oral administration, apalutamide, its N-desmethyl metabolite (M3), and an inactive carboxylic acid metabolite (M4) accounted for most 14C in plasma (45%, 44%, and 3%, respectively). Apalutamide elimination was slow, with a mean plasma half-life of 151-178 hours. The mean cumulative recovery of total 14C over 70 days postdose was 64.6% in urine and 24.3% in feces. The urinary excretion of apalutamide, M3, and M4 was 1.2%, 2.7%, and 31.1% of dose, respectively. Fecal excretion of apalutamide, M3, and M4 was 1.5%, 2.0%, and 2.4% of dose, respectively. Seventeen apalutamide metabolites and six main metabolic clearance pathways were identified. In vitro studies confirmed CYP2C8 and CYP3A4 roles in apalutamide metabolism.

Spatial distributions of Southern Ocean mesozooplankton communities have been resilient to long-term surface warming.

The biogeographic response of oceanic planktonic communities to climatic change has a large influence on the future stability of marine food webs and the functioning of global biogeochemical cycles. Temperature plays a pivotal role in determining the distribution of these communities and ocean warming has the potential to cause major distributional shifts, particularly in polar regions where the thermal envelope is narrow. We considered the impact of long-term ocean warming on the spatial distribution of Southern Ocean mesozooplankton communities through examining plankton abundance in relation to sea surface temperature between two distinct periods, separated by around 60 years. Analyses considered 16 dominant mesozooplankton taxa (in terms of biomass and abundance) in the southwest Atlantic sector of the Southern Ocean, from net samples and in situ temperature records collected during the Discovery Investigations (1926-1938) and contemporary campaigns (1996-2013). Sea surface temperature was found to have increased significantly by 0.74°C between the two eras. The corresponding sea surface temperature at which community abundance peaked was also significantly higher in contemporary times, by 0.98°C. Spatial projections indicated that the geographical location of community peak abundance had remained the same between the two eras despite the poleward advance of sea surface isotherms. If the community had remained within the same thermal envelope as in the 1920s-1930s, community peak abundance would be 500 km further south in the contemporary era. Studies in the northern hemisphere have found that dominant taxa, such as calanoid copepods, have conserved their thermal niches and tracked surface isotherms polewards. The fact that this has not occurred in the Southern Ocean suggests that other selective pressures, particularly food availability and the properties of underlying water masses, place greater constraints on spatial distributions in this region. It further demonstrates that this community is thermally resilient to present levels of sea surface warming.

Complement-induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction.

Polymicrobial sepsis in mice causes myocardial dysfunction after generation of the complement anaphylatoxin, complement component 5a (C5a). C5a interacts with its receptors on cardiomyocytes (CMs), resulting in redox imbalance and cardiac dysfunction that can be functionally measured and quantitated using Doppler echocardiography. In this report we have evaluated activation of MAPKs and Akt in CMs exposed to C5a in vitro and after cecal ligation and puncture (CLP) in vivo In both cases, C5a in vitro caused activation (phosphorylation) of MAPKs and Akt in CMs, which required availability of both C5a receptors. Using immunofluorescence technology, activation of MAPKs and Akt occurred in left ventricular (LV) CMs, requiring both C5a receptors, C5aR1 and -2. Use of a water-soluble p38 inhibitor curtailed activation in vivo of MAPKs and Akt in LV CMs as well as the appearance of cytokines and histones in plasma from CLP mice. When mouse macrophages were exposed in vitro to LPS, activation of MAPKs and Akt also occurred. The copresence of the p38 inhibitor blocked these activation responses. Finally, the presence of the p38 inhibitor in CLP mice reduced the development of cardiac dysfunction. These data suggest that polymicrobial sepsis causes cardiac dysfunction that appears to be linked to activation of MAPKs and Akt in heart.-Fattahi, F., Kalbitz, M., Malan, E. A., Abe, E., Jajou, L., Huber-Lang, M. S., Bosmann, M., Russell, M. W., Zetoune, F. S., Ward, P. A. Complement-induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction.

Complement Destabilizes Cardiomyocyte Function In Vivo after Polymicrobial Sepsis and In Vitro.

There is accumulating evidence during sepsis that cardiomyocyte (CM) homeostasis is compromised, resulting in cardiac dysfunction. An important role for complement in these outcomes is now demonstrated. Addition of C5a to electrically paced CMs caused prolonged elevations of intracellular Ca(2+) concentrations during diastole, together with the appearance of spontaneous Ca(2+) transients. In polymicrobial sepsis in mice, we found that three key homeostasis-regulating proteins in CMs were reduced: Na(+)/K(+)-ATPase, which is vital for effective action potentials in CMs, and two intracellular Ca(2+) concentration regulatory proteins, that is, sarcoplasmic/endoplasmic reticulum calcium ATPase 2 and the Na(+)/Ca(2+) exchanger. Sepsis caused reduced mRNA levels and reductions in protein concentrations in CMs for all three proteins. The absence of either C5a receptor mitigated sepsis-induced reductions in the three regulatory proteins. Absence of either C5a receptor (C5aR1 or C5aR2) diminished development of defective systolic and diastolic echocardiographic/Doppler parameters developing in the heart (cardiac output, left ventricular stroke volume, isovolumic relaxation, E' septal annulus, E/E' septal annulus, left ventricular diastolic volume). We also found in CMs from septic mice the presence of defective current densities for Ik1, l-type calcium channel, and Na(+)/Ca(2+) exchanger. These defects were accentuated in the copresence of C5a. These data suggest complement-related mechanisms responsible for development of cardiac dysfunction during sepsis.

Experimental Malaria in Pregnancy Induces Neurocognitive Injury in Uninfected Offspring via a C5a-C5a Receptor Dependent Pathway.

The in utero environment profoundly impacts childhood neurodevelopment and behaviour. A substantial proportion of pregnancies in Africa are at risk of malaria in pregnancy (MIP) however the impact of in utero exposure to MIP on fetal neurodevelopment is unknown. Complement activation, in particular C5a, may contribute to neuropathology and adverse outcomes during MIP. We used an experimental model of MIP and standardized neurocognitive testing, MRI, micro-CT and HPLC analysis of neurotransmitter levels, to test the hypothesis that in utero exposure to malaria alters neurodevelopment through a C5a-C5aR dependent pathway. We show that malaria-exposed offspring have persistent neurocognitive deficits in memory and affective-like behaviour compared to unexposed controls. These deficits were associated with reduced regional brain levels of major biogenic amines and BDNF that were rescued by disruption of C5a-C5aR signaling using genetic and functional approaches. Our results demonstrate that experimental MIP induces neurocognitive deficits in offspring and suggest novel targets for intervention.

Genomic signatures of evolution in Nautilus-An endangered living fossil.

Living fossils are survivors of previously more diverse lineages that originated millions of years ago and persisted with little morphological change. Therefore, living fossils are model organisms to study both long-term and ongoing adaptation and speciation processes. However, many aspects of living fossil evolution and their persistence in the modern world remain unclear. Here, we investigate three major aspects of the evolutionary history of living fossils: cryptic speciation, population genetics and effective population sizes, using members of the genera Nautilus and Allonautilus as classic examples of true living fossils. For this, we analysed genomewide ddRAD-Seq data for all six currently recognized nautiloid species throughout their distribution range. Our analyses identified three major allopatric Nautilus clades: a South Pacific clade, subdivided into three subclades with no signs of admixture between them; a Coral Sea clade, consisting of two genetically distinct populations with significant admixture; and a widespread Indo-Pacific clade, devoid of significant genetic substructure. Within these major clades, we detected five Nautilus groups, which likely correspond to five distinct species. With the exception of Nautilus macromphalus, all previously described species are at odds with genomewide data, testifying to the prevalence of cryptic species among living fossils. Detailed FST analyses further revealed significant genome-wide and locus-specific signatures of selection between species and differentiated populations, which is demonstrated here for the first time in a living fossil. Finally, approximate Bayesian computation (ABC) simulations suggest large effective population sizes, which may explain the low levels of population differentiation commonly observed in living fossils.

Complement-induced activation of the cardiac NLRP3 inflammasome in sepsis.

Cardiac dysfunction develops during sepsis in humans and rodents. In the model of polymicrobial sepsis induced by cecal ligation and puncture (CLP), we investigated the role of the NLRP3 inflammasome in the heart. Mouse heart homogenates from sham-procedure mice contained high mRNA levels of NLRP3 and IL-1ß. Using the inflammasome protocol, exposure of cardiomyocytes (CMs) to LPS followed by ATP or nigericin caused release of mature IL-1ß. Immunostaining of left ventricular frozen sections before and 8 h after CLP revealed the presence of NLRP3 and IL-1ß proteins in CMs. CLP caused substantial increases in mRNAs for IL-1ß and NLRP3 in CMs which are reduced in the absence of either C5aR1 or C5aR2. After CLP, NLRP3-/- mice showed reduced plasma levels of IL-1ß and IL-6. In vitro exposure of wild-type CMs to recombinant C5a (rC5a) caused elevations in both cytosolic and nuclear/mitochondrial reactive oxygen species (ROS), which were C5a-receptor dependent. Use of a selective NOX2 inhibitor prevented increased cytosolic and nuclear/mitochondrial ROS levels and release of IL-1ß. Finally, NLRP3-/- mice had reduced defects in echo/Doppler parameters in heart after CLP. These studies establish that the NLRP3 inflammasome contributes to the cardiomyopathy of polymicrobial sepsis.-Kalbitz, M., Fattahi, F., Grailer, J. J., Jajou, L., Malan, E. A., Zetoune, F. S., Huber-Lang, M., Russell, M. W., Ward, P. A. Complement-induced activation of the cardiac NLRP3 inflammasome in sepsis.

Cutting edge: critical role for C5aRs in the development of septic lymphopenia in mice.

In the early stages of sepsis, lymphocytes undergo apoptosis, resulting in lymphopenia and immunosuppression. The trigger for septic lymphopenia is unknown. Using the polymicrobial model of murine sepsis, we investigated the role of C5a receptors in septic lymphopenia. In wild-type mice, cecal ligation and puncture resulted in splenocyte apoptosis and significant lymphopenia after 3 d, which was not observed in C5aR1(-/-) or C5aR2(-/-) mice. Our data show that mouse neutrophils exposed to recombinant mouse C5a cause release of histones in a dose-dependent and time-dependent manner. Histone levels in spleen were significantly elevated following cecal ligation and puncture but were reduced by the absence of C5aR1. Histones induced significant lymphocyte apoptosis in vitro. Ab-mediated neutralization of histones prevented the development of lymphopenia in sepsis. Together, these results describe a new pathway of septic lymphopenia involving complement and extracellular histones. Targeting of this pathway may have therapeutic benefit for patients with sepsis or other serious illness.