[Strong as death or how efferocytotic macrophages promote the resolution of inflammation]. / « Fort comme la mort ¼,* où comment l'efferocytose contrôle la résolution de l'inflammation.

The resolution of inflammation is an active process leading to the restoration of tissue homeostasis. A critical step in the initiation of this process is the elimination of apoptotic immune cells by macrophages. This well-organized process, called efferocytosis, involves four different steps, namely the attraction of macrophages to the site where the cells die, the recognition of apoptotic cells, their internalization and their digestion leading to the activation of different metabolic pathways. All these steps are responsible for the reprogramming of macrophages towards a pro-resolving profile. Efferocytic macrophages produce several factors involved in the resolution of inflammation. These factors include lipids (i.e., specialized pro-resolving mediators such as lipoxins), and proteins (e.g., IL-10 or TGF-ß). Here, we describe the different steps of efferocytosis and the mechanisms responsible for both macrophage reprogramming and the release of pro-resolving factors. These factors may represent a new therapeutic approach, called resolution therapy.

Title: « Fort comme la mort ¼,* où comment l'efferocytose contrôle la résolution de l'inflammation. Abstract: L'arrêt de la réponse inflammatoire, ou résolution de l'inflammation, est considéré aujourd'hui comme un processus actif lié à la production (ou à la libération) de composés anti-inflammatoires aussi appelés composés pro-résolutifs. L'évènement permettant d'enclencher la résolution de l'inflammation est l'élimination des cellules immunitaires apoptotiques par les macrophages, un processus nommé efferocytose, dont l'altération est à l'origine de différentes maladies. Dans cette synthèse, nous décrivons les étapes de cette efferocytose et les mécanismes qui en résultent et permettent de stopper l'inflammation. Nous évoquerons également de nouvelles pistes thérapeutiques fondées sur les facteurs pro-résolutifs : la thérapie résolutive.

Resolved Psoriasis with Abundant Oleic Acid in Stratum Corneum Exhibits Lower T-Cell-Driven IL-17 Signature.

Relapses of psoriasis involve T cells that stem and survive in the skin. Inherited from previous flares, the tissue-resident memory T cells are epidermal IL-17-producing CD8+ and IL-22-producing CD4+ T cells. Because the capacity of resident memory T cells to take in fatty acids is essential for their residence and function, the surface composition of fatty acids may affect underlying T-cell populations. In patients treated with biologics, we used gas chromatography/mass spectrometry to decipher the fatty acid composition in both resolved and nonlesional sites. Skin T cells were activated by OKT-3 in explants from the same body sites to perform bulk transcriptomic analysis (Nanostring). The fatty acid composition differed between skin from healthy donors and normal-looking skin of patients with psoriasis but not further between nonlesional and resolved skin. Patients in whom the resolved skin was rich in oleic acid had lower T-cell-driven IL-17 epidermal transcriptomic signature upon activation of T cells in skin explants. The skin lipid composition is linked with the functions of the underlying epidermal T cells. Testing the modulating effect of custom fatty acids on skin resident T cells could help with coming closer to disease oblivion in inflammatory skin diseases.

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

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.

Pro-Resolving Factor Administration Limits Cancer Progression by Enhancing Immune Response Against Cancer Cells.

Cancers are consequences of cellular dysfunction leading to an aberrant cellular multiplication and proliferation, subsequently yielding metastasis formation. Inflammatory reaction, with immune cell recruitment, is the main defense against precancerous lesions. However, an inflammatory environment also favors cancer cell progression, with cancer cell evasion from immune surveillance, leading to cancer development. Current therapeutic strategies enhance this natural immune response in order to restore immunosurveillance. The variety of these strategies is a predominant source of inflammatory mediators used by cancer cells to grow, differentiate, and migrate, therefore encouraging metastasis formation. For this reason, during cancer progression, limiting inflammation appears to be an innovative strategy to avoid the escape of cancer cells and potentially enhance the efficacy of antitumor therapies. Thus, this study aims to investigate the impact of administering pro-resolving factors (SuperMApo® drug candidate), which are inducers of inflammation resolution, in the framework of cancer treatment. We have observed that administering pro-resolving mediators issued from apoptotic cell efferocytosis by macrophages controlled peritoneal cancer progression by limiting cancer cell dissemination to the blood and mesenteric lymph nodes. This observation has been linked to an increase of macrophage mobilization in both peritoneal cavity and mesenteric lymph nodes. This control is associated to a restricted immunosuppressive myeloid cell circulation and to an IFN-γ-specific anti-tumor T-cell response. Altogether, these results suggest that administering proresolving factors could provide a new additional therapeutic alternative to control cancer progression.