Heme and hemolysis in innate immunity: adding insult to injury

Martins, Rui; Knapp, Sylvia

doi:10.1016/j.coi.2017.10.005

Cited by 56 publications

(50 citation statements)

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“…Erythrophagocytosis inhibits macrophage-mediated autophagy via heme oxygenase-1 (HO-1) expression. Increased RBC damage or intravascular hemolysis can lead to acute heme accumulation in macrophages (29). In response, macrophages promptly upregulate a number of protective mechanisms: these protective responses involve heme catabolism by HO-1 and iron sequestration by ferritin (29,30).…”

Section: Resultsmentioning

confidence: 99%

Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients

Dai

Cai

Wang

et al. 2020

mBio

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Macrophage dysfunction is associated with increased tuberculosis (TB) susceptibility in patients with human immunodeficiency virus (HIV) infection. However, the mechanisms underlying how HIV infection impairs macrophage function are unclear. Here, we found that levels of autoantibodies against red blood cells (RBCs) were significantly elevated in patients with HIV as determined by direct antiglobulin test (DAT). DAT positivity was significantly associated with TB incidence in both univariate and multivariate analyses (odds ratio [OR] = 11.96 [confidence interval {CI}, 4.68 to 30.93] and 12.65 [3.33 to 52.75], respectively). Ex vivo analysis showed that autoantibodies against RBCs enhanced erythrophagocytosis and thus significantly impaired macrophage bactericidal function against intracellular Mycobacterium tuberculosis. Mechanistically, autoantibody-mediated erythrophagocytosis increased heme oxygenase-1 (HO-1) expression, which inhibited M. tuberculosis-induced autophagy in macrophages. Silencing ATG5, a key component for autophagy, completely abrogated the effect of erythrophagocytosis on macrophage bactericidal activity against M. tuberculosis. In conclusion, we have demonstrated that HIV infection increases autoantibody-mediated erythrophagocytosis. This process impairs macrophage bactericidal activity against M. tuberculosis by inhibiting HO-1-associated autophagy. These findings reveal a novel mechanism as to how HIV infection increases TB susceptibility. IMPORTANCE HIV infection significantly increases TB susceptibility due to CD4 T-cell loss and macrophage dysfunction. Although it is relatively clear that CD4 T-cell loss represents a direct effect of HIV infection, the mechanism underlying how HIV infection dampens macrophage function is unknown. Here, we show that HIV infection enhances autoantibody-mediated erythrophagocytosis, which dampens macrophage bactericidal activity against TB by inhibiting HO-1-associated autophagy. Our findings reveal a novel mechanism explaining how HIV infection increases susceptibility to TB. We propose that DAT could be a potential measure to identify HIV patients who are at high TB risk and who would be suitable for anti-TB chemotherapy preventive treatment.

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Section: Resultsmentioning

confidence: 99%

Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients

Dai

Cai

Wang

et al. 2020

mBio

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“…[74][75] A recent study additionally suggests that free heme decreases mobility of macrophages and prevents adequate pathogen clearance. 76 To this end, disrupted hemostasis can have two detrimental outcomes which assist bacterial outgrowth: release of iron [77][78] that benefits bacterial replication, along with release of heme that may impair macrophage-mediated phagocytosis of pathogenic bacteria. 76 As urinary samples from VUR patients have been obtained at minimum one month after infection, longitudinal follow up over the longer course of time is needed to further understand if quantitative changes of these urinary proteins are short term or remains altered over prolonged period of time.…”

Section: Discussionmentioning

confidence: 99%

Characterizing Patients with Recurrent Urinary Tract Infections in Vesicoureteral Reflux: A Pilot Study of the Urinary Proteome

Vitko

Cho

Kostel

et al. 2020

Molecular & Cellular Proteomics

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Recurrent urinary tract infections (UTIs) pose a significant burden on the health care system. Underlying mechanisms predisposing children to UTIs and associated changes in the urinary proteome are not well understood. We aimed to investigate the urinary proteome of a subset of children who have vesicoureteral reflux (VUR) and recurrent UTIs because of their risk of developing infection-related renal damage. Improving diagnostic modalities to identify UTI risk factors would significantly alter the clinical management of children with VUR. We profiled the urinary proteomes of 22 VUR patients with low grade VUR (1–3 out of 5), a history of recurrent UTIs, and renal scarring, comparing them to those obtained from 22 age-matched controls. Urinary proteins were analyzed by mass spectrometry followed by protein quantitation based on spectral counting. Of the 2,551 proteins identified across both cohorts, 964 were robustly quantified, as defined by meeting criteria with spectral count (SC) ≥2 in at least 7 patients in either VUR or control cohort. Eighty proteins had differential expression between the two cohorts, with 44 proteins significantly up-regulated and 36 downregulated (q <0.075, FC ≥1.2). Urinary proteins involved in inflammation, acute phase response (APR), modulation of extracellular matrix (ECM), and carbohydrate metabolism were altered among the study cohort.

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“…This study provides clinical evidence of diagnostic and prognostic value of HO-1 during the progression of sepsis. It is now well established from a variety of studies, that HO-1 can be induced by hemin, which may further cause oxidative stress and inflammation, especially in the progression of acute organ injury 19,20 . Heme, as a ubiquitous compound of human tissue, is involved in physiology and metabolism.…”

Section: Discussionmentioning

confidence: 99%

The diagnostic and prognostic value of heme oxygenase 1 in sepsis-induced acute kidney injury: a cross-sectional observational study

Xia¹,

Zhang²,

Liu³

et al. 2019

Preprint

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Background Sepsis patients suffer from severe inflammatory and poor prognosis. Local inflammation resulted from sepsis is found to trigger organ injury, such as acute kidney injury (AKI). We conducted a cross-sectional observational study to examine the diagnostic and prognostic role of serum heme oxygenase 1 (HO-1) on sepsis-induced AKI. Methods The 83 enrolled patients were initially divided into two groups with no AKI (NAKI) and sepsis-induced AKI group (SAKI) based on whether had AKI. Then the patients were concretely divided into four groups: septic shock and AKI group (SS+AKI group), sepsis-induced AKI group (S+AKI group), septic shock group (SS group), and sepsis group (S group. The venous blood was sampled within 24 hours after diagnosis of sepsis. We detected the serum HO-1 and laboratory indicators by enzyme-linked immunosorbent assay. The 28-day survival status was observed between the HO-1 high- and low-level patients grouped by the median of HO-1 concentration 41.33U/L. Results We found that there were statistically significant results of SOFA score and admission time between SAKI and NAKI group (p<0.05). The level of HO-1 in SAKI group was obviously elevated as compared with NAKI group (p<0.05). It was remarkable to show that HO-1 level was remarkably higher in SS+AKI group than that in other three groups (p<0.05). In All groups, HO-1 positively correlates with SOFA score, Scr, Hb, APTT, Urea, and TnI (p<0.05). In SS+AKI group, HO-1 was positively associated with SOFA score, Scr, AKI stage, γ-GT, and FDP (p<0.05). In S+AKI, HO-1 level was positively related to the level of Scr, AKI stage, and ALP (p<0.05). In SS group, SOFA score was in negative correlation to HO-1 (p<0.05). The AUC of HO-1 and serum creatinine was 0.824 (95% CI: 0.703-0.944) and 0.778 (95% CI: 0.658-0.919) separately. The AUC of combined with HO-1 and serum creatinine was 0.864 (95% CI: 0.761-0.968). The survival analysis showed that sepsis patients with high HO-1 level had a higher mortality rate compared with patients with low HO-1 expression. Conclusions The findings from this study make contributions to clinical value of HO-1, suggesting that HO-1 plays a diagnostic and prognostic role in sepsis-induced AKI.

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Heme and hemolysis in innate immunity: adding insult to injury

Cited by 56 publications

References 56 publications

Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients

Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients

Characterizing Patients with Recurrent Urinary Tract Infections in Vesicoureteral Reflux: A Pilot Study of the Urinary Proteome

The diagnostic and prognostic value of heme oxygenase 1 in sepsis-induced acute kidney injury: a cross-sectional observational study

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