Macrophage metabolic reprogramming presents a therapeutic target in lupus nephritis

Jing, Chenzhi; Castro‐Dopico, Tomas; Richoz, Nathan; Tuong, Zewen Kelvin; Ferdinand, John R.; Lok, Laurence S.C.; Loudon, Kevin; Banham, Gemma D.; Mathews, Rebeccah J.; Cader, M Zaeem; Fitzpatrick, Susan F.; Bashant, Kathleen R.; Kaplan, Mariana J.; Kaser, Arthur; Johnson, Randall S.; Murphy, Michael P.; Siegel, Richard M.; Clatworthy, Menna R.

doi:10.1073/pnas.2000943117

Cited by 102 publications

(67 citation statements)

References 55 publications

(79 reference statements)

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“…Immune complexes comprised of IgG-bound antigens may further contribute to vascular leakage and cytokine storm via CD16/FcγRIII engagement (72). Cross-linking of FcγRs by IgG ICs induces macrophage activation and a switch in metabolic programming to glycolysis, accompanied by hypoxia-inducible factor HIF-1α dependent cytokine release, mirroring outcomes observed in IC-mediated autoinflammatory disease (73). In this context, it is notable that monocytes from patients with severe COVID-19 show high expression of HIF-1α and associated target genes, compared with healthy controls.…”

Section: Self-reactive Antibodies and Fcγr Responses In Immune-enhanced Pathologymentioning

confidence: 98%

Severe Clinical Worsening in COVID-19 and Potential Mechanisms of Immune-Enhanced Disease

Hussman

2021

Front. Med.

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Infection by the novel SARS-CoV-2 coronavirus produces a range of outcomes, with the majority of cases producing mild or asymptomatic effects, and a smaller subset progressing to critical or fatal COVID-19 disease featuring severe acute respiratory distress. Although the mechanisms driving severe disease progression remain unknown, it is possible that the abrupt clinical deterioration observed in patients with critical disease corresponds to a discrete underlying expansion of viral tropism, from infection of cells comprising respiratory linings and alveolar epithelia to direct infection and activation of inflammatory monocytes and macrophages. Dysregulated immune responses could then contribute to disease severity. This article discusses the potential role of monocyte/macrophage (Mo/Mϕ) infection by SARS-CoV-2 in mediating the immune response in severe COVID-19. Additional mechanisms of immune-enhanced disease, comprising maladaptive immune responses that may aggravate rather than alleviate severity, are also discussed. Severe acute clinical worsening in COVID-19 patients may be influenced by the emergence of antibodies that participate in hyperinflammatory monocyte response, release of neutrophil extracellular traps (NETs), thrombosis, platelet apoptosis, viral entry into Fc gamma receptor (FcγR)-expressing immune cells, and induction of autoantibodies with cross-reactivity against host proteins. While the potential roles of Mo/Mϕ infection and immune-enhanced pathology in COVID-19 are consistent with a broad range of clinical and laboratory findings, their prominence remains tentative pending further validation. In the interim, these proposed mechanisms present immediate avenues of inquiry that may help to evaluate the safety of candidate vaccines and antibody-based therapeutics, and to support consideration of pathway-informed, well-tolerated therapeutic candidates targeting the dysregulated immune response.

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Section: Self-reactive Antibodies and Fcγr Responses In Immune-enhanced Pathologymentioning

confidence: 98%

Severe Clinical Worsening in COVID-19 and Potential Mechanisms of Immune-Enhanced Disease

Hussman

2021

Front. Med.

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“…Trained immunity has previously been identified as a phenomenon through which the innate immunity could contribute to inflammatory diseases [5], participating both to disease initiation and maintenance or aggravation of deleterious environment. For example, in atherosclerosis and systemic lupus erythematous, monocytes/macrophages share several features observed in MS patient macrophages such as increased expression of pro-inflammatory cytokines [8,48], metabolic rewiring [8,27], and overrepresentation of pro-inflammatory CD14 + CD16 + cells [48,58].…”

Section: Trained Innate Immunitymentioning

confidence: 99%

Dysregulated functional and metabolic response in multiple sclerosis patient macrophages correlate with a more inflammatory state, reminiscent of trained immunity

Fransson

Bachelin

Deknuydt

et al. 2021

Preprint

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In multiple sclerosis (MS), immune cells invade the central nervous system and destroy myelin. Macrophages contribute to demyelination and myelin repair, and their role in each process depends on their ability to acquire specific phenotypes in response to external signals. Here, we assess whether defects in MS patient macrophage responses may lead to increased inflammation or lack of neuro-regenerative effects.To test this hypothesis, CD14+CD16- monocytes from MS patients and healthy controls were activated in vitro to obtain homeostatic-like, pro-inflammatory and pro-regenerative macrophages. Myelin phagocytic capacity and surface molecule expression of CD14, CD16 and HLA-DR were evaluated with flow cytometry. In parallel, macrophages were assessed through RNA sequencing and metabolomics.We observed that MS patient monocytes ex vivo recapitulate their preferential activation toward a CD16+ phenotype, a subset of pro-inflammatory cells present in MS lesions. Even in the absence of pro-inflammatory stimuli, MS patient macrophages exhibit a pro-inflammatory transcriptomic profile with higher levels of cytokine/chemokine suggesting increased recruitment capacities. Interestingly, MS patient macrophages exhibit a specific metabolic signature with a mitochondrial energy metabolism blockage resulting in a shift from oxidative phosphorylation to glycolysis. Furthermore, we observe a failure to up-regulate apoptosis effector genes in the pro inflammatory state suggesting a longer-lived pro-inflammatory macrophage population.Our results highlight an intrinsic defect of MS patient macrophages that provide evidence of innate immune cell memory in MS.

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“…As shown in Figure 4A, the expressions of 20 cytokines and chemokines such as IL-6, IL-8, IL-17C, IL-32, IL-19, IL21, IL-1A, IL-24, TNFSF18, TNFSF4, CSF1, CSF3, CCL2, CCL7, CXCL1, CXCL2, CXCL12, CXCL13, CCL20, and CXCL16 were significantly upregulated. TNFSF4 has been reported to be upregulated in metabolic reprogramming in macrophages stimulated with immune complex (ova-IC) (121). CSF1 is upregulated in TI (122), and CSF3 secreted from EC is a major source to promote myelopoiesis during systemic inflammation (123).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, as shown in Table 3, 15 cytokine and chemokine receptors including IL3RA, IL4R, IL7R, IL13RA2, IL15RA, IL17RE, IL20RB, CCRL1, CXCR4, TNFRSF10A, TNFRSF10B, TNFRSF10C, TNFRSF10D, TNFRSF11A, IFNGR2 were upregulated in in MERS-CoV-infected HMEC. Similar to TNFSF4, TNFSF10, a ligand for TNFRSF10A, TNFRSF10B, TNFRSF10C, TNFRSF10D, has been reported to be upregulated in metabolic reprogramming in macrophages stimulated with immune complex (Ova-IC) (121) and in neutrophils stimulated by a prototypic TI stimulus BCG vaccine for EC adhesion (124). Taken together, these results have demonstrated that at least 20 cytokines and chemokines are selectively upregulated as MERS-CoV infection process progresses, suggesting the enhancement of innate immune responses as one of the key features of TI.…”

Section: Resultsmentioning

confidence: 99%

Endothelial Immunity Trained by Coronavirus Infections, DAMP Stimulations and Regulated by Anti-Oxidant NRF2 May Contribute to Inflammations, Myelopoiesis, COVID-19 Cytokine Storms and Thromboembolism

Shao

Saredy

et al. 2021

Front. Immunol.

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To characterize transcriptomic changes in endothelial cells (ECs) infected by coronaviruses, and stimulated by DAMPs, the expressions of 1311 innate immune regulatomic genes (IGs) were examined in 28 EC microarray datasets with 7 monocyte datasets as controls. We made the following findings: The majority of IGs are upregulated in the first 12 hours post-infection (PI), and maintained until 48 hours PI in human microvascular EC infected by middle east respiratory syndrome-coronavirus (MERS-CoV) (an EC model for COVID-19). The expressions of IGs are modulated in 21 human EC transcriptomic datasets by various PAMPs/DAMPs, including LPS, LPC, shear stress, hyperlipidemia and oxLDL. Upregulation of many IGs such as nucleic acid sensors are shared between ECs infected by MERS-CoV and those stimulated by PAMPs and DAMPs. Human heart EC and mouse aortic EC express all four types of coronavirus receptors such as ANPEP, CEACAM1, ACE2, DPP4 and virus entry facilitator TMPRSS2 (heart EC); most of coronavirus replication-transcription protein complexes are expressed in HMEC, which contribute to viremia, thromboembolism, and cardiovascular comorbidities of COVID-19. ECs have novel trained immunity (TI), in which subsequent inflammation is enhanced. Upregulated proinflammatory cytokines such as TNFα, IL6, CSF1 and CSF3 and TI marker IL-32 as well as TI metabolic enzymes and epigenetic enzymes indicate TI function in HMEC infected by MERS-CoV, which may drive cytokine storms. Upregulated CSF1 and CSF3 demonstrate a novel function of ECs in promoting myelopoiesis. Mechanistically, the ER stress and ROS, together with decreased mitochondrial OXPHOS complexes, facilitate a proinflammatory response and TI. Additionally, an increase of the regulators of mitotic catastrophe cell death, apoptosis, ferroptosis, inflammasomes-driven pyroptosis in ECs infected with MERS-CoV and the upregulation of pro-thrombogenic factors increase thromboembolism potential. Finally, NRF2-suppressed ROS regulate innate immune responses, TI, thrombosis, EC inflammation and death. These transcriptomic results provide novel insights on the roles of ECs in coronavirus infections such as COVID-19, cardiovascular diseases (CVD), inflammation, transplantation, autoimmune disease and cancers.

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Macrophage metabolic reprogramming presents a therapeutic target in lupus nephritis

Cited by 102 publications

References 55 publications

Severe Clinical Worsening in COVID-19 and Potential Mechanisms of Immune-Enhanced Disease

Severe Clinical Worsening in COVID-19 and Potential Mechanisms of Immune-Enhanced Disease

Dysregulated functional and metabolic response in multiple sclerosis patient macrophages correlate with a more inflammatory state, reminiscent of trained immunity

Endothelial Immunity Trained by Coronavirus Infections, DAMP Stimulations and Regulated by Anti-Oxidant NRF2 May Contribute to Inflammations, Myelopoiesis, COVID-19 Cytokine Storms and Thromboembolism

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