Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

Chang, C.; Goods, Brittany A.; Askenase, Michael H.; Hammond, Matthew D.; Renfroe, Stephen C.; Steinschneider, Arthur F.; Landreneau, Margaret J; Ai, Youxi; Beatty, Hannah E.; Costa, Luís Henrique Angenendt da; Mack, Matthias; Sheth, Kevin N; Greer, David M.; Hüttner, Anita; Coman, Daniel; Hyder, Fahmeed; Ghosh, Sourav; Rothlin, Carla V.; Love, J. Christopher; Sansing, Lauren H

doi:10.1172/jci95612

Cited by 140 publications

(177 citation statements)

References 96 publications

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“…Conversely, those with low early CCL2 that then increased by 72 h after ICH had better outcomes at 90 days. Preclinical work has identified important contributions of macrophages to recovery in ICH, ischemic stroke, and mild traumatic brain injury through mechanisms such as phagocytosis of cellular debris, promotion of angiogenesis, and secretion of growth factors. These temporal patterns are consistent with the 6 h data and also provide clinical evidence for potential later beneficial effects of monocyte‐macrophage recruitment in patients.…”

Section: Discussionmentioning

confidence: 99%

CCL2 and CXCL10 are associated with poor outcome after intracerebral hemorrhage

Landreneau

Mullen

Messé

et al. 2018

Ann Clin Transl Neurol

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ObjectiveIntracerebral hemorrhage carries a high mortality and survivors are frequently left with significant disability. Immunological mechanisms may play an important role in hemorrhage‐induced brain injury, however, research linking these mechanisms with clinical outcome remains limited. We aim to identify serum inflammatory mediators that are associated with outcome after intracerebral hemorrhage in order to translate data from experimental models to a patient cohort and identify potential targets worthy of reverse translation.MethodsA prospective cohort study at two comprehensive stroke centers enrolled patients with spontaneous intracerebral hemorrhage. Peripheral blood was collected at 6, 24, and 72 h from onset. Functional outcome was assessed at 90 days using the modified Rankin Scale (mRS). Serum inflammatory mediators were measured using multiplex ELISA. Multivariable modeling identified serum biomarkers independently associated with functional outcome at 90 days.Results115 patients completed the study. At 6 h after onset, patients with elevated CCL2 had worse mRS score at day 90 (OR 4.07, 95% CI 1.27–13.10, P = 0.02) after adjusting for age, gender, ICH volume, IVH, infratentorial location and NIHSS score. At 24 and 72 h after onset, elevation in CXCL10 was independently associated with worse 90 days mRS score (24 h: OR 8.08, 95% CI 2.69–24.30, P < 0.001; 72 h: OR 3.89, 95% CI 1.12–13.49, P = 0.03).InterpretationAcute and subacute elevations in specific immune factors are associated with poor outcome, highlighting potential pathways that may contribute to ongoing brain injury in patients with intracerebral hemorrhage.

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Section: Discussionmentioning

confidence: 99%

CCL2 and CXCL10 are associated with poor outcome after intracerebral hemorrhage

Landreneau

Mullen

Messé

et al. 2018

Ann Clin Transl Neurol

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“…However, emerging findings suggest equally important protective features. Several studies have defined that hemoglobin‐derived heme could reshape the phenotype of macrophages, which is implicated in reduction of atherosclerosis and tissue injury in the brain 10,11,13‐15 . Certain amounts of heme are often exposed to the intestinal microenvironment in IBD.…”

Section: Discussionmentioning

confidence: 99%

“…Tissue micro‐environment is crucial for shaping the identities of macrophages 8,9 . Heme, a metabolite of erythrocyte degradation, was reported to play protective roles in hemorrhagic diseases like stroke and atherosclerosis by providing anti‐inflammatory features and restorative functions for macrophages 10‐15 . Bleeding within the mucosa is commonly seen in both patients and mice with UC, resulting in heme accumulating in intestine mucosal 16 .…”

Section: Introductionmentioning

confidence: 99%

Heme protects intestinal mucosal barrier in DSS‐induced colitis through regulating macrophage polarization in both HO‐1‐dependent and HO‐1‐independent way

Zhang

et al. 2020

FASEB j.

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Hemoglobin‐derived heme was reported to play protective roles in hemorrhagic diseases by modulating the macrophages toward recovery. Mucosal bleeding is one of the pathological features of inflammatory bowel diseases (IBD). However, whether heme provides anti‐inflammatory profiles in macrophages, thus contributing to the intestinal mucosal barrier protection, is unclear. In the current study, we investigated the beneficial effects of heme on DSS‐induced colitis mice and explored the underlying mechanisms. In vivo, systemic heme supplementation by hemin injection relieved intestinal inflammation and remedied intestinal mucosal barrier damage by correcting abnormal intestinal macrophage polarization. In vitro, we confirmed the reciprocally regulating effects of hemin on M1/M2 macrophage polarization in BMDM. Intriguingly, with knockdown of HO‐1, the inhibiting effects of hemin on M1 polarization were maintained, while the promoting effects on M2 polarization were reversed. Further research proved that hemin repressed the inflammatory profiles in macrophages through inhibiting the translocation of NF‐κB p65 by disrupting IRF5‐NF‐κB p65 complex formation in Spi‐C‐dependent way. In conclusion, these results showed that the modification of colon tissue microenvironment with heme supplementation plays a protective role in DSS‐induced colitis mice through regulating the macrophage polarization in both HO‐1‐dependent and HO‐1‐independent way, indicating a new choice to therapeutically modulate the macrophage function and prevent IBD.

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“…Mo/MΦ cells also directly contribute to the process of DVT resolution through a variety of mechanisms associated with the pro-resolving state. They phagocytize erythrocytes, platelets, matrix debris, and the cellular remains from apoptosis, such as NETs which likely contribute to stage 1 clot stability but delay resolution [61,[102][103][104]. Pro-resolving Mo/MΦ cells directly express fibrinolytic and collagenolytic enzymes that allow them to invade the thrombus tissue, particularly uPA and MMP9 [105][106][107][108].…”

Section: Monocyte-derived Macrophages and Thrombus Resolutionmentioning

confidence: 99%

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

Nicklas

Gordon

Henke

2020

IJMS

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Venous thromboembolism (VTE) is a pathology encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) associated with high morbidity and mortality. Because patients often present after a thrombus has already formed, the mechanisms that drive DVT resolution are being investigated in search of treatment. Herein, we review the current literature, including the molecular mechanisms of fibrinolysis and collagenolysis, as well as the critical cellular roles of macrophages, neutrophils, and endothelial cells. We propose two general models for the operation of the immune system in the context of venous thrombosis. In early thrombus resolution, neutrophil influx stabilizes the tissue through NETosis. Meanwhile, macrophages and intact neutrophils recognize the extracellular DNA by the TLR9 receptor and induce fibrosis, a complimentary stabilization method. At later stages of resolution, pro-inflammatory macrophages police the thrombus for pathogens, a role supported by both T-cells and mast cells. Once they verify sterility, these macrophages transform into their pro-resolving phenotype. Endothelial cells both coat the stabilized thrombus, a necessary early step, and can undergo an endothelial-mesenchymal transition, which impedes DVT resolution. Several of these interactions hold promise for future therapy. already progressed past the point of anticoagulant efficacy [12,13]. Thus, there is potential clinical utility in investigating and controlling the process by which DVTs resolve in order to provide better care to these later-stage patients, with less bleeding risk. Overview of Venous Thrombus Development in HumansThe time sequence of DVT development and resolution was correctly suggested as early as 1962, based on empirical stains that detected changes in the nanoscopic roughness of clotted material [14]. As Lendrum et. al. remarked, "we consider that the intracytoplasmic granules, which we think are engulfed fibrin, seen in pulmonary phagocytes and in the endothelium of arteries and veins containing thrombus, are better shown by this (methyl-scarlet-blue) method than by any of the others." In fresh clot (whether in deep veins or in diabetic kidneys), platelets and erythrocytes are initially linked in a fine mesh yielding a relatively smooth surface (stage 1). A mat of the medium-textured fibrin replaces the initial thrombus (stage 2), which is gradually replaced by much coarser collagen (stage 3). This staging of clot development quickly became the basis of a pathological guide to grade thrombi [15]. The current three-stage refinement of the DVT grading scheme indicates that the turnover of erythrocyte-rich to fibrin-rich clot in humans is complete approximately seven days after the initial thrombotic event [16], whereas fibrin deposition commences after one day [17]. Various leukocytes, initially neutrophils and later macrophages, are believed to control this progression of DVTs development from a mass of erythrocytes, to fibrin, and finally to collagen [18]. Infiltrating T-lymphocytes and macrophages conta...

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Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

Cited by 140 publications

References 96 publications

CCL2 and CXCL10 are associated with poor outcome after intracerebral hemorrhage

CCL2 and CXCL10 are associated with poor outcome after intracerebral hemorrhage

Heme protects intestinal mucosal barrier in DSS‐induced colitis through regulating macrophage polarization in both HO‐1‐dependent and HO‐1‐independent way

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

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