Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory functions and clearance of apoptotic cells

Salina, Ana Carolina Guerta; dos-Santos, Douglas; Rodrigues, Tamara Silva; Fortes-Rocha, Marlon; Filho, Edismauro Garcia Freitas; Alzamora-Terrel, Daniel L; Castro, Icaro MS; Fraga-Silva, Thais Fernanda de Campos; Lima, Mikhael HF de; Nascimento, Daniele C.; Silva, Camila M.; Toller-Kawahisa, Juliana E; Becerra, Amanda; Oliveira, Samuel; Caetité, Diego B; Almeida, Letícia de; Ishimoto, Adriene Y; Lima, Thais M.; Martins, Ronaldo B.; Veras, Flávio P.; Amaral, Natália Brasil; Giannini, Marcela C; Bonjorno, Letícia Pastorelli; Lopes, M. Beatriz S.; Benatti, Maíra Nilson; Batah, Sabrina Setembre; Santana, Rodrigo de Carvalho; Vilar, Fernando Crivelenti; Martins, Maria Auxiliadora Parreiras; Assad, Rodrigo Luppino; deAlmeida, Sergio CL; Oliveira, Fabíola Reis; Neto, Eurico Arruda; Cunha, Thiago M.; Alves‐Filho, José C.; Bonato, Vânia L D; Cunha, Fernando Q.; Fabro, Alexandre Todorovic; Nakaya, Hidehiko; Zamboni, Dario S.; Louzada‐Júnior, Paulo; Oliveira, Renê DR de; Cunha, Larissa D.

doi:10.7554/elife.74443

Cited by 36 publications

(20 citation statements)

References 53 publications

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“…4, C and D). Moreover, RNase L KO THP-1 cells had higher levels of IL-6 and CXCL10 secretion than WT cells when cocultured with SARS-CoV-2–infected Vero cells, which support SARS-CoV-2 replication ( 72 , 73 ) (Fig. 4E and fig.…”

Section: Resultsmentioning

confidence: 68%

Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children

Lee

Pen

Yatim

et al. 2023

Science

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Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1 , OAS2 , or RNASEL in five unrelated children with MIS-C. The cytosolic dsRNA-sensing OAS1 and OAS2 generate 2′-5′-linked oligoadenylates (2-5A) that activate the ssRNA-degrading RNase L. Monocytic cell lines and primary myeloid cells with OAS1 , OAS2 , or RNASEL deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or SARS-CoV-2 stimulation. Exogenous 2-5A suppresses cytokine production in OAS1- but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by MAVS deficiency. Recessive OAS–RNase L deficiencies in these patients unleash the production of SARS-CoV-2–triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.

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Section: Resultsmentioning

confidence: 68%

Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children

Lee

Pen

Yatim

et al. 2023

Science

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“…Our encouraging results obtained with SuperMApo in CIA support its use in RA. One may also extend the indications of resolution therapy to acute inflammatory diseases with non-resolving inflammation, such as the severe form of severe acute respiratory syndrome coronavirus (SARS-CoV2) infection ( 128 ). Indeed, the blockade of anti-inflammatory macrophage reprogramming by SARS-CoV2-infected apoptotic cells has been recently reported ( 128 ).…”

Section: Discussionmentioning

confidence: 99%

“…One may also extend the indications of resolution therapy to acute inflammatory diseases with non-resolving inflammation, such as the severe form of severe acute respiratory syndrome coronavirus (SARS-CoV2) infection ( 128 ). Indeed, the blockade of anti-inflammatory macrophage reprogramming by SARS-CoV2-infected apoptotic cells has been recently reported ( 128 ). The SARS-CoV2 hyper-inflammatory syndrome ( 129 ) could result from the absence of macrophage reprogramming after efferocytosis of SARS-CoV2-infected dying cells.…”

Section: Discussionmentioning

confidence: 99%

Resolution therapy: Harnessing efferocytic macrophages to trigger the resolution of inflammation

Saas

Vetter²,

Maraux³

et al. 2022

Front. Immunol.

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Several chronic inflammatory diseases are associated with non-resolving inflammation. Conventional anti-inflammatory drugs fail to completely cure these diseases. Resolution pharmacology is a new therapeutic approach based on the use of pro-resolving mediators that accelerate the resolution phase of inflammation by targeting the productive phase of inflammation. Indeed, pro-resolving mediators prevent leukocyte recruitment and induce apoptosis of accumulated leukocytes. This approach is now called resolution therapy with the introduction of complex biological drugs and cell-based therapies. The main objective of resolution therapy is to specifically reduce the duration of the resolution phase to accelerate the return to homeostasis. Under physiological conditions, macrophages play a critical role in the resolution of inflammation. Indeed, after the removal of apoptotic cells (a process called efferocytosis), macrophages display anti-inflammatory reprogramming and subsequently secrete multiple pro-resolving factors. These factors can be used as resolution therapy. Here, we review the different mechanisms leading to anti-inflammatory reprogramming of macrophages after efferocytosis and the pro-resolving factors released by these efferocytic macrophages. We classify these mechanisms in three different categories: macrophage reprogramming induced by apoptotic cell-derived factors, by molecules expressed by apoptotic cells (i.e., “eat-me” signals), and induced by the digestion of apoptotic cell-derived materials. We also evoke that macrophage reprogramming may result from cooperative mechanisms, for instance, implicating the apoptotic cell-induced microenvironment (including cellular metabolites, specific cytokines or immune cells). Then, we describe a new drug candidate belonging to this resolution therapy. This candidate, called SuperMApo, corresponds to the secretome of efferocytic macrophages. We discuss its production, the pro-resolving factors present in this drug, as well as the results obtained in experimental models of chronic (e.g., arthritis, colitis) and acute (e.g., peritonitis or xenogeneic graft-versus-host disease) inflammatory diseases.

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“…Many viruses, including SARS-CoV-2, enhance infectivity by usurping both the physiological cell-cell fusion and efferocytosis, disrupting biological barriers [75,86]. For example, the SARS-CoV-2 virus thrives in infected cells and likely inhibits their clearance, causing inflammation and barrier dysfunction [87]. In addition, SARS-CoV-2 promotes pathological cell-cell fusion and syncytia formation by generating cell membrane pores via the PRRA (proline-arginine-arginine-alanine) motif situated at the furin-cleavage site (FCS).…”

Section: Intestinal Barriermentioning

confidence: 99%

Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies

Sfera

Osorio

Hazan³

et al. 2022

Endocrines

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Similar to previous pandemics, COVID-19 has been succeeded by well-documented post-infectious sequelae, including chronic fatigue, cough, shortness of breath, myalgia, and concentration difficulties, which may last 5 to 12 weeks or longer after the acute phase of illness. Both the psychological stress of SARS-CoV-2 infection and being diagnosed with COVID-19 can upregulate cortisol, a stress hormone that disrupts the efferocytosis effectors, macrophages, and natural killer cells, leading to the excessive accumulation of senescent cells and disruption of biological barriers. This has been well-established in cancer patients who often experience unrelenting fatigue as well as gut and blood–brain barrier dysfunction upon treatment with senescence-inducing radiation or chemotherapy. In our previous research from 2020 and 2021, we linked COVID-19 to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) via angiotensin II upregulation, premature endothelial senescence, intestinal barrier dysfunction, and microbial translocation from the gastrointestinal tract into the systemic circulation. In 2021 and 2022, these hypotheses were validated and SARS-CoV-2-induced cellular senescence as well as microbial translocation were documented in both acute SARS-CoV-2 infection, long COVID, and ME/CFS, connecting intestinal barrier dysfunction to disabling fatigue and specific infectious events. The purpose of this narrative review is to summarize what is currently known about host immune responses to translocated gut microbes and how these responses relate to fatiguing illnesses, including long COVID. To accomplish this goal, we examine the role of intestinal and blood–brain barriers in long COVID and other illnesses typified by chronic fatigue, with a special emphasis on commensal microbes functioning as viral reservoirs. Furthermore, we discuss the role of SARS-CoV-2/Mycoplasma coinfection in dysfunctional efferocytosis, emphasizing some potential novel treatment strategies, including the use of senotherapeutic drugs, HMGB1 inhibitors, Toll-like receptor 4 (TLR4) blockers, and membrane lipid replacement.

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Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory functions and clearance of apoptotic cells

Cited by 36 publications

References 53 publications

Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children

Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children

Resolution therapy: Harnessing efferocytic macrophages to trigger the resolution of inflammation

Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies

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