Drugging the efferocytosis process: concepts and opportunities

Mehrotra, Parul; Ravichandran, Kodi S.

doi:10.1038/s41573-022-00470-y

Cited by 146 publications

(139 citation statements)

References 229 publications

(250 reference statements)

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“…This would prevent a necrotic response to a controlled, cell death in the body, however, in atherosclerosis this mechanism is altered. This efferocytosis impairment is responsible for the chronic inflammation in a number of inflammatory diseases, and there are extremely limited treatments currently available for this, however, the use of miR-33 could be a future therapeutic avenue targeting defective efferocytosis, due to the role of the abca1 gene in functional efferocytosis ( Mehrotra and Ravichandran, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Posing the rationale for synthetic lipoxin mimetics as an adjuvant treatment to gold standard atherosclerosis therapies

Millar

Gaetano²

2023

Front. Pharmacol.

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Atherosclerosis is a progressive, multifactorial inflammatory, and dyslipidaemic disease, responsible for the majority of cardiovascular diseases globally. The chronic inflammation is the main driver of the initiation and progression of such disease, as a result of an imbalanced lipid metabolism and an ineffective immune response to attenuate the inflammatory component. The importance of inflammation resolution is being increasingly recognised in atherosclerosis and cardiovascular disease. It has a complex mechanism consisting of multiple stages, including restoring an effective removal of apoptotic bodies (efferocytosis) and their degradation (effero-metabolism), a macrophage phenotype switching towards resolving phenotypes, and the promotion of tissue healing and regeneration. The low-grade inflammation associated with atherosclerosis development is a driving force in disease exacerbation, and hence inflammation resolution is a key area of research. In this review, we explore the complex disease pathogenesis and its many contributing factors to gain a greater understanding of the disease and identify the current and potential therapeutic targets. First-line treatments and their efficacy will also be discussed in detail, to highlight the emerging field of resolution pharmacology. Despite the great efforts made by current gold-standard treatments, such as lipid-lowering and glucose-lowering drugs, they remain ineffective at tackling residual inflammatory risk and residual cholesterol risk. Resolution pharmacology represents a new era of atherosclerosis therapy, as endogenous ligands associated with inflammation resolution are exploited for their pharmacological benefits in a more potent and longer-acting manner. Novel FPR2-agonists, such as synthetic lipoxin analogues, provide an exciting new approach to enhance the pro-resolving response of the immune system and subsequently end the pro-inflammatory response to allow for an anti-inflammatory and pro-resolving environment for tissue healing, regeneration, and return to homeostasis.

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Section: Discussionmentioning

confidence: 99%

Posing the rationale for synthetic lipoxin mimetics as an adjuvant treatment to gold standard atherosclerosis therapies

Millar

Gaetano²

2023

Front. Pharmacol.

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“…This was unexpected since the transcriptional profile of Type 2 polarized eosinophils was shown to display marked overlap and similarity with that of M2-polarized macrophages ( 6 ). The different transcriptional phenotype of eosinophils and macrophages in response to IL-4 and apoptotic cells likely results from the fact that macrophages express a large and different repertoire of receptors and intracellular molecules that can bind, engulf and digest apoptotic cells ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of Type 1 and Type 2 mouse eosinophil activation by apoptotic cells

et al. 2022

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Eosinophils are multifunctional, evolutionary conserved leukocytes that are involved in a plethora of responses ranging from regulation of tissue homeostasis, host defense and cancer. Although eosinophils have been studied mostly in the context of Type 2 inflammatory responses, it is now evident that they participate in Type 1 inflammatory responses and can respond to Type 1 cytokines such as IFN-γ. Notably, both Type 1- and Type 2 inflammatory environments are characterized by tissue damage and cell death. Collectively, this raises the possibility that eosinophils can interact with apoptotic cells, which can alter eosinophil activation in the inflammatory milieu. Herein, we demonstrate that eosinophils can bind and engulf apoptotic cells. We further show that exposure of eosinophils to apoptotic cells induces marked transcriptional changes in eosinophils, which polarize eosinophils towards an anti-inflammatory phenotype that is associated with wound healing and cell migration. Using an unbiased RNA sequencing approach, we demonstrate that apoptotic cells suppress the inflammatory responses of eosinophils that were activated with IFN-γ + E. coli (e.g., Type 1 eosinophils) and augment IL-4-induced eosinophil activation (e.g., Type 2 eosinophils). These data contribute to the growing understanding regarding the heterogeneity of eosinophil activation patterns and highlight apoptotic cells as potential regulators of eosinophil polarization.

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“…We were the first in 2001 to propose the use of apoptotic cells as a cell-based therapy approach ( 42 ). However, this is out of the scope of this review (for recent reviews please refer to ( 21 , 24 , 43 ). Here, we want to focus on the contribution of macrophages to the resolution therapy.…”

Section: Efferocytosis As a Critical Step Triggering The Resolution P...mentioning

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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Drugging the efferocytosis process: concepts and opportunities

Cited by 146 publications

References 229 publications

Posing the rationale for synthetic lipoxin mimetics as an adjuvant treatment to gold standard atherosclerosis therapies

Posing the rationale for synthetic lipoxin mimetics as an adjuvant treatment to gold standard atherosclerosis therapies

Differential regulation of Type 1 and Type 2 mouse eosinophil activation by apoptotic cells

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

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