title: Metabolic dysfunction in lymphocytes promotes postoperative morbidity.
abstract: Perioperative lymphopenia has been linked with an increased risk of postoperative infectious complications, but the mechanisms remain unclear. We tested the hypothesis that bioenergetic dysfunction is an important mechanism underlying lymphopenia, impaired functionality and infectious complications. In two cohorts of patients (61-82 years old) undergoing orthopaedic joint replacement (n=417 and 328, respectively), we confirmed prospectively that preoperative lymphopenia (≤1.3 x 10(9)·l(-1); <20% white cell count; prevalence 15-18%) was associated with infectious complications (relative risk 1.5 (95% confidence interval 1.1-2.0); P=0.008) and prolonged hospital stay. Lymphocyte respirometry, mitochondrial bioenergetics and function were assessed (n=93 patients). Postoperative lymphocytes showed a median 43% fall (range: 26-65%; P=0.029; n=13 patients) in spare respiratory capacity, the extra capacity available to produce energy in response to stress. This was accompanied by reduced glycolytic capacity. A similar hypometabolic phenotype was observed in lymphocytes sampled preoperatively from chronically lymphopenic patients (n=21). This hypometabolic phenotype was associated with functional lymphocyte impairment including reduced T-cell proliferation, lower intracellular cytokine production and excess apoptosis induced by a range of common stressors. Glucocorticoids, which are ubiquitously elevated for a prolonged period postoperatively, generated increased levels of mitochondrial reactive oxygen species, activated caspase-1 and mature interleukin (IL)-1β in human lymphocytes, suggesting inflammasome activation. mRNA transcription of the NLRP1 inflammasome was increased in lymphocytes postoperatively. Genetic ablation of the murine NLRP3 inflammasome failed to prevent glucocorticoid-induced lymphocyte apoptosis and caspase-1 activity, but increased NLRP1 protein expression. Our findings suggest that the hypometabolic phenotype observed in chronically lymphopenic patients and/or acquired postoperatively increases the risk of postoperative infection through glucocorticoid activation of caspase-1 via the NLRP1 inflammasome.
authors.affiliation: Clinical Physiology, Department of Medicine, University College London, London WC1E 6BT, U.K.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Edwards
authors.affiliation: Clinical Physiology, Department of Medicine, University College London, London WC1E 6BT, U.K.
authors.forename: Pervez
authors.initials: P
authors.lastname: Sultan
authors.affiliation: Clinical Physiology, Department of Medicine, University College London, London WC1E 6BT, U.K.
authors.forename: Ana Gutierrez
authors.initials: AG
authors.lastname: del Arroyo
authors.affiliation: Clinical Physiology, Department of Medicine, University College London, London WC1E 6BT, U.K.
authors.forename: John
authors.initials: J
authors.lastname: Whittle
authors.affiliation: Clinical Physiology, Department of Medicine, University College London, London WC1E 6BT, U.K.
authors.forename: Shamir N
authors.initials: SN
authors.lastname: Karmali
authors.affiliation: Clinical Physiology, Department of Medicine, University College London, London WC1E 6BT, U.K.
authors.forename: S Ramani
authors.initials: SR
authors.lastname: Moonesinghe
authors.affiliation: Clinical Physiology, Department of Medicine, University College London, London WC1E 6BT, U.K.
authors.forename: Fares S
authors.initials: FS
authors.lastname: Haddad
authors.affiliation: Clinical Physiology, Department of Medicine, University College London, London WC1E 6BT, U.K.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Mythen
authors.affiliation: Clinical Physiology, Department of Medicine, University College London, London WC1E 6BT, U.K.
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
authors.affiliation: Clinical Physiology, Department of Medicine, University College London, London WC1E 6BT, U.K. g.ackland@ucl.ac.uk.
authors.forename: Gareth L
authors.initials: GL
authors.lastname: Ackland
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D019643:Arthroplasty, Replacement / Q000009:adverse effects* / Q000295:instrumentation / Q000401:mortality; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007595:Joint Prosthesis / Q000009:adverse effects*; D053208:Kaplan-Meier Estimate; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008231:Lymphopenia / Q000150:complications* / Q000175:diagnosis / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010641:Phenotype; D016459:Prosthesis-Related Infections / Q000175:diagnosis / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D051017:Apoptosis Regulatory Proteins; D005938:Glucocorticoids; D058847:Inflammasomes
keywords: apoptosis; inflammasome; lymphocyte; metabolism; mitochondria; sepsis