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Tumor-associated macrophages (TAM) represent the main immune cell population of the tumor microenvironment in most cancer. For decades, TAM have been the focus of intense investigation to understand how they modulate the tumor microenvironment and their implication in therapy failure. One consensus is that TAM are considered to exclusively originate from circulating monocyte precursors released from the bone marrow, fitting the original dogma of tissue-resident macrophage ontogeny. A second consensus proposed that TAM harbor either a classically activated M1 or alternatively activated M2 polarization profile, with almost opposite anti- and pro-tumoral activity respectively. These fundamental pillars are now revised in face of the latest discoveries on macrophage biology. Embryonic-derived macrophages were recently characterized as major contributors to the pool of tissue-resident macrophages in many tissues. Their turnover with macrophages derived from precursors of adult hematopoiesis seems to follow a regulation at the subtissular level. This has shed light on an ever more complex macrophage diversity in the tumor microenvironment than once thought and raise the question of their respective implication in tumor development compared to classical monocyte-derived macrophages. These recent advances highlight that TAM have actually not fully revealed their usefulness and deserve to be reconsidered. Understanding the link between TAM ontogeny and their various functions in tumor growth and interaction with the immune system represents one of the future challenges for cancer therapy.

Targeting the post-translational modification enzyme QPCTL prevents the protection of CCL2 and CCL7 from N-terminal degradation, inactivates their chemotactic function and limits the recruitment of pro-tumoral macrophages.

In mice, monocytes (Mo) are conventionally described as CX3CR1 classical Mo (CMo) and CX3CR1 non-classical Mo (NCMo) based on the expression of EGFP in Cx3cr1 mice and by analogy with human CX3CR1 expression. Although this terminology is widely used, it may not reflect the expression of CX3CR1 on Mo subsets. Using an unsupervised multiparametric analysis of blood Mo in steady state and after sterile peritonitis, we observed that CX3CR1 expression did not discriminate the CMo from the NCMo subsets. Our results highlight that despite being a reliable reporter to discriminate Mo subpopulations, EGFP level in Cx3cr1 mice does not reflect CX3CR1 expression measured by a fluorescently-labeled CX3CL1 chemokine and a CX3CR1 specific antibody. In conclusion, authors should be cautious not to identify murine classical and non-classical Mo as CX3CR1 and CX3CR1 but rather use alternative markers such as the combination of Ly6C and CD43.

In most cancers, myeloid cells represent the major component of the immune microenvironment. Deciphering the impact of these cells on tumor growth and in response to various anti-tumor therapies is a key issue. Many studies have elucidated the role of tumor-associated monocytes and tumor-associated macrophages (TAM) in tumor development, angiogenesis, and therapeutic failure. In contrast, tumor dendritic cells (DC) are associated with tumor antigen uptake and T-cell priming. Myeloid subpopulations display differences in ontogeny, state of differentiation and distribution within the neoplastic tissue, making them difficult to study. The development of high-dimensional genomic and cytometric analyses has unveiled the large functional diversity of myeloid cells. Important fundamental insights on the biology of myeloid cells have also been provided by a boom in functional fluorescent imaging techniques, in particular for TAM. These approaches allow the tracking of cell behavior in native physiological environments, incorporating spatio-temporal dimensions in the study of their functional activity. Nevertheless, tracking myeloid cells within the TME remains a challenging process as many markers overlap between monocytes, macrophages, DC, and neutrophils. Therefore, perfect discrimination between myeloid subsets remains impossible to date. Herein we review the specific functions of myeloid cells in tumor development unveiled by image-based tracking, the limits of fluorescent reporters commonly used to accurately track specific myeloid cells, and novel combinations of myeloid-associated fluorescent reporters that better discriminate the relative contributions of these cells to tumor biology according to their origin and tissue localization.

Monocytes are phagocytic effector cells in the blood and precursors of resident and inflammatory tissue macrophages. The aim of the current study was to analyse and compare their contribution to innate immune surveillance of the lung in the steady state with macrophage and dendritic cells (DC). ECFP and EGFP transgenic reporters based upon Csf1r and Cx3cr1 distinguish monocytes from resident mononuclear phagocytes. We used these transgenes to study the migratory properties of monocytes and macrophages by functional imaging on explanted lungs. Migratory monocytes were found to be either patrolling within large vessels of the lung or locating at the interface between lung capillaries and alveoli. This spatial organisation gives to monocytes the property to capture fluorescent particles derived from both vascular and airway routes. We conclude that monocytes participate in steady-state surveillance of the lung, in a way that is complementary to resident macrophages and DC, without differentiating into macrophages. White blood cells form part of the immune system, which protects the body against infectious diseases and other harmful agents. Some of these cells, including ‘mononuclear phagocytes’, can reside within different tissues of the body, such as the lungs. Other less specialized cells, called monocytes, circulate in the bloodstream. It had long been thought that once these monocytes had taken up residence in a tissue, they could only develop into tissue-resident phagocytes. Several researchers, however, recently reported that monocytes can also reside within tissues without becoming more specialized. Nevertheless, it remained unclear what these cells did when they were in these tissues. Rodero, Poupel, Loyher et al. investigated the activities of tissue-resident monocytes found in the lungs of mice. First, mice were genetically engineered to produce fluorescent markers that meant that their monocytes could be easily distinguished from the mononuclear phagocytes in their lungs when viewed under a microscope. Rodero, Poupel, Loyher et al. then showed that the monocytes and the other mononuclear phagocytes localized to different regions of the lung. Further experiments showed that these two groups of cells also moved around the lungs in different ways. The tissue-resident monocytes surveyed both the blood vessels and airways, while the other tissue-resident mononuclear phagocytes only surveyed the airways. These findings show that lung-resident monocytes perform a different role to those found in the bloodstream. The findings also open the way to improving our understanding of what tissue-resident monocytes do in other organs, and in healthy or diseased animals.

The triggering receptor expressed on myeloid cells 1 (TREM-1) drives inflammatory responses in several cardiovascular diseases but its role in abdominal aortic aneurysm (AAA) remains unknown. Our objective was to explore the role of TREM-1 in a mouse model of angiotensin II-induced (AngII-induced) AAA. TREM-1 expression was detected in mouse aortic aneurysm and colocalized with macrophages. Trem1 gene deletion (Apoe-/-Trem1-/-), as well as TREM-1 pharmacological blockade with LR-12 peptide, limited both AAA development and severity. Trem1 gene deletion attenuated the inflammatory response in the aorta, with a reduction of Il1b, Tnfa, Mmp2, and Mmp9 mRNA expression, and led to a decreased macrophage content due to a reduction of Ly6Chi classical monocyte trafficking. Conversely, antibody-mediated TREM-1 stimulation exacerbated Ly6Chi monocyte aorta infiltration after AngII infusion through CD62L upregulation and promoted proinflammatory signature in the aorta, resulting in worsening AAA severity. AngII infusion stimulated TREM-1 expression and activation on Ly6Chi monocytes through AngII receptor type I (AT1R). In human AAA, TREM-1 was detected and TREM1 mRNA expression correlated with SELL mRNA expression. Finally, circulating levels of sTREM-1 were increased in patients with AAA when compared with patients without AAA. In conclusion, TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in humans.

Hypercholesterolemia is a major risk factor for atherosclerosis and associated cardiovascular diseases. The liver plays a key role in the regulation of plasma cholesterol levels and hosts a large population of tissue-resident macrophages known as Kupffer cells (KCs). KCs are located in the hepatic sinusoids where they ensure key functions including blood immune surveillance. However, how KCs homeostasis is affected by the build-up of cholesterol-rich lipoproteins that occurs in the circulation during hypercholesterolemia remains unknown. Here, we show that embryo-derived KCs (EmKCs) accumulate large amounts of lipoprotein-derived cholesterol, in part through the scavenger receptor CD36, and massively expand early after the induction of hypercholesterolemia. After this rapid adaptive response, EmKCs exhibit mitochondrial oxidative stress and their numbers gradually diminish while monocyte-derived KCs (MoKCs) with reduced cholesterol-loading capacities seed the KC pool. Decreased proportion of EmKCs in the KC pool enhances liver cholesterol content and exacerbates hypercholesterolemia, leading to accelerated atherosclerotic plaque development. Together, our data reveal that KC homeostasis is perturbed during hypercholesterolemia, which in turn alters the control of plasma cholesterol levels and increases atherosclerosis. The liver contains a large population of macrophages called Kupffer cells. Here the authors show that during hypercholesterolemia, the homeostasis of Kupffer cells is disrupted, leading to further elevation of plasma cholesterol levels and increased atherosclerosis.

Visceral leishmaniasis (VL) is a systemic disease with multifaceted clinical manifestations, including neurological signs, however, the involvement of the nervous system during VL is underestimated. Accordingly, we investigated both brain infection and inflammation in a mouse model of VL. Using bioluminescent Leishmania donovani and real-time 2D-3D imaging tools, we strikingly detected live parasites in the brain, where we observed a compartmentalized dual-phased inflammation pattern: an early phase during the first two weeks post-infection, with the prompt arrival of neutrophils and Ly6C high macrophages in an environment presenting a variety of pro-inflammatory mediators (IFN-γ, IL-1β, CXCL-10/CXCR-3, CCL-7/CCR-2), but with an intense anti-inflammatory response, led by IL-10; and a re-inflammation phase three months later, extremely pro-inflammatory, with novel upregulation of mediators, including IL-1β, TNF-α and MMP-9. These new data give support and corroborate previous studies connecting human and canine VL with neuroinflammation and blood-brain barrier disruption, and conclusively place the brain among the organs affected by this parasite. Altogether, our results provide convincing evidences that Leishmania donovani indeed infects and inflames the brain.

The cells of the mononuclear phagocyte system are essential for the correct healing of adult skin wounds, but their specific functions remain ill-defined. The absence of granulation tissue immediately after skin injury makes it challenging to study the role of mononuclear phagocytes at the initiation of this inflammatory stage. To study their recruitment and migratory behavior within the wound bed, we developed a new model for real-time in vivo imaging of the wound, using transgenic mice that express green and cyan fluorescent proteins and specifically target monocytes. Within hours after the scalp injury, monocytes invaded the wound bed. The complete abrogation of this infiltration in monocyte-deficient CCR2(-/-) mice argues for the involvement of classical monocytes in this process. Monocyte infiltration unexpectedly occurred as early as neutrophil recruitment did and resulted from active release from the bloodstream toward the matrix through microhemorrhages rather than transendothelial migration. Monocytes randomly scouted around the wound bed, progressively slowed down, and stopped. Our approach identified and characterized a rapid and earlier than expected wave of monocyte infiltration and provides a novel framework for investigating the role of these cells during early stages of wound healing.

Muscle injury triggers inflammation in which infiltrating mononuclear phagocytes are crucial for tissue regeneration. The interaction of the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axis that guides phagocyte infiltration is incompletely understood. Here, we show that CX3CR1 deficiency promotes muscle repair and rescues Ccl2 −/− mice from impaired muscle regeneration as a result of altered macrophage function, not infiltration. Transcriptomic analysis of muscle mononuclear phagocytes reveals that Apolipoprotein E (ApoE) is upregulated in mice with efficient regeneration. ApoE treatment enhances phagocytosis by mononuclear phagocytes in vitro , and restores phagocytic activity and muscle regeneration in Ccl2 −/− mice. Because CX3CR1 deficiency may compensate for defective CCL2-dependant monocyte recruitment by modulating ApoE-dependent macrophage phagocytic activity, targeting CX3CR1 expressed by macrophages might be a powerful therapeutic approach to improve muscle regeneration. Chemokine-driven infiltration of inflammatory macrophages is central to the muscle regenerative response to injury. Here the authors show that the function of infiltrating macrophages is also important as notexin-induced muscle injury in mice is rescued by CX3CR1 knockout owing to enhanced ApoE production.