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Neutralizing antibodies (nAbs) are pivotal in developing fast, broadly protective therapeutics against novel pandemic viruses. Despite their well-known direct neutralization capacity, their effector mechanisms via Fc receptors remain poorly understood. Identifying the types of effector cells engaged in antibody-mediated effector functions is essential for regulating their activities. Using the lymphocytic choriomeningitis virus (LCMV), we show that nAbs obtained from immune sera or monoclonal LCMV-specific nAbs show dependency on Fc receptors. We demonstrate that therapy with nAbs is highly protective in the presence of patrolling monocytes. These monocytes bind nAbs primarily via FcγRIV, targeting virus-infected cells, and thereby limiting virus propagation. Depleting patrolling monocytes or blocking FcγRIV resulted in a substantial loss of virus control by nAbs, indicating the pivotal role of patrolling monocytes in the antiviral activity of these antibodies. In conclusion, our findings highlight that, alongside direct neutralization, nAbs primarily exert their effects through the involvement of patrolling monocytes.

Long-Living Individuals (LLIs) delay aging and are less prone to chronic inflammatory reactions. Whether a distinct monocytes and macrophages repertoire is involved in such a characteristic remains unknown. Previous studies from our group have shown high levels of the host defense BPI Fold Containing Family B Member 4 (BPIFB4) protein in the peripheral blood of LLIs. Moreover, a polymorphic variant of the gene associated with exceptional longevity ( ) confers protection from cardiovascular diseases underpinned by low-grade chronic inflammation, such as atherosclerosis. We hypothesize that BPIFB4 may influence monocytes pool and macrophages skewing, shifting the balance toward an anti-inflammatory phenotype. We profiled circulating monocytes in 52 LLIs (median-age 97) and 52 healthy volunteers (median-age 55) using flow cytometry. If the frequency of total monocyte did not change, the intermediate CD14++CD16+ monocytes counts were lower in LLIs compared to control adults. Conversely, non-classical CD14+CD16++ monocyte counts, which are M2 macrophage precursors with an immunomodulatory function, were found significantly associated with the LLIs' state. In a differentiation assay, supplementation of the LLIs' plasma enhanced the capacity of monocytes, either from LLIs or controls, to acquire a paracrine M2 phenotype. A neutralizing antibody against the phosphorylation site (ser 75) of BPIFB4 blunted the M2 skewing effect of the LLIs' plasma. These data indicate that LLIs carry a peculiar anti-inflammatory myeloid profile, which is associated with and possibly sustained by high circulating levels of BPIFB4. Supplementation of recombinant BPIFB4 may represent a novel means to attenuate inflammation-related conditions typical of unhealthy aging.

Patrolling monocytes (PMo) are the organism’s preeminent intravascular guardians by their continuous search of damaged endothelial cells and harmful microparticles for their removal and to restore homeostasis. This surveillance is accomplished by PMo crawling on the apical side of the endothelium through regulated interactions of integrins and chemokine receptors with their endothelial ligands. We propose that the search mode governs the intravascular motility of PMo in vivo in a similar way to T cells looking for antigen in tissues. Signs of damage to the luminal side of the endothelium (local death, oxidized LDL, amyloid deposits, tumor cells, pathogens, abnormal red cells, etc.) will change the diffusive random towards a Lèvy-like crawling enhancing their recognition and clearance by PMo damage receptors as the integrin αMβ2 and CD36. This new perspective can help identify new actors to promote unique PMo intravascular actions aimed at maintaining endothelial fitness and combating harmful microparticles involved in diseases as lung metastasis, Alzheimer’s angiopathy, vaso-occlusive disorders, and sepsis.

Background Evidence on the changes in the absolute counts of monocyte subpopulations in sepsis is missing. Methods Firstly, absolute counts of circulating CD14 pos /HLA-DR pos /CD45 pos monocytes were measured by flow cytometry in 70 patients with Gram-negative sepsis and in 10 healthy volunteers. In the second phase, immunophenotyping was performed and the absolute count of circulating inflammatory monocytes and of circulating CD14 dim /CD16 pos /CD45 pos patrolling monocytes were measured in another 55 patients and 10 healthy volunteers. Measurements were repeated on days 3, 7, and 10. Results were correlated with survival after 28 days. Results Greater numbers of CD14 pos /HLA-DR pos /CD45 pos monocytes were found on day 1 in survivors compared to nonsurvivors ( p = 0.030). Receiver operating characteristic (ROC) analysis showed that a cutoff higher than 337 cells/mm 3 on day 1 could discriminate between survivors and nonsurvivors with a positive predictive value (PPV) of 91.1%. Logistic regression including Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE) II score showed that an absolute count greater than 337 cells/mm 3 was independently associated with unfavorable outcome (odds ratio (OR) 0.19, p = 0.050). The absolute counts of inflammatory and of CD14 dim /CD16 pos /CD45 pos monocytes were greater in patients than healthy controls during the entire 10 days of follow-up. The absolute counts on day 3 of CD14 dim /CD16 pos /CD45 pos monocytes were greater in survivors than nonsurvivors ( p = 0.027). ROC analysis revealed that the cutoff at 27 cells/mm 3 could discriminate between survivors and nonsurvivors with PPV of 94.1%. Logistic regression including age, SOFA score, and APACHE II score showed that an absolute count greater than 27 cells/mm 3 was independently associated with unfavorable outcome (OR 0.06, p = 0.033). Logistic regression analysis showed that intra-abdominal infection on day 1 was predictive of low CD14 dim / CD16 pos /CD45 pos count on day 3. Conclusion Circulating counts of inflammatory and patrolling monocytes are greatly increased in Gram-negative sepsis. Absolute counts of CD14 pos /HLA-DR pos /CD45 pos monocytes on day 1 and CD14 dim /CD16 pos /CD45 pos monocytes on day 3 are independently associated with final outcome. Trial registration ClinicalTrials.gov, NCT01223690 . Registered retrospectively on 18 October 2010.

Metastasis is responsible for most of the cancer-associated deaths and proceeds through multiple steps. Several lines of evidence have established an indispensable involvement of macrophages present at the primary tumor sites in various steps of metastasis, from primary tumor growth to its intravasation into circulation. The lungs encompass a large, dense vascular area and, therefore, are vulnerable to metastasis, particularly, hematogenous ones arising from various types of neoplasms. Lung tissues constitutively contain several types of tissue-resident macrophages and circulating monocytes to counteract potentially harmful exogenous materials, which directly reach through the airway. Recent advances have provided an insight into the ontogenetic, phenotypic, and functional heterogeneity of these lung macrophage and monocyte populations, under resting and inflammatory conditions. In this review, we discuss the ontogeny, trafficking dynamics, and functions of these pulmonary macrophages and monocytes and their potential roles in lung metastasis and measures to combat lung metastasis by targeting these populations.

Monocytes are important players to combat the ubiquitously present fungus Aspergillus fumigatus. Recruitment of monocytes to sites of fungal A. fumigatus infection has been shown in vivo. Upon exposure to A. fumigatus in vitro, purified murine and human blood monocytes secrete inflammatory cytokines and fungicidal mediators. Mononuclear tissue phagocytes are phenotypically and functionally different from those circulating in the blood and their role in antifungal defenses is much less understood. In this study, we identified a population of migrating CD43+ monocytes in cells isolated from rat distal lungs. These cells are phenotypically different from alveolar macrophages and show distinct locomotory behavior on the surface of primary alveolar cells resembling previously described endothelial patrolling monocytes. Upon challenge, the CD43+ monocytes internalized A. fumigatus conidia resulting in inhibition of their germination and hyphal growth. Thus, migrating lung monocytes might play an important role in local defense against pulmonary pathogens.

Excitotoxicity underlies neuronal death in many neuropathological disorders, such as Alzheimer’s disease and multiple sclerosis. In murine models of these diseases, disruption of CX3CR1 signaling has thus far generated data either in favor or against a neuroprotective role of this crucial regulator of microglia and monocyte functions. In this study, we investigated the recruitment of circulating PU.1-expressing cells following sterile excitotoxicity and delineated the CX3CR1-dependent neuroprotective functions of circulating monocytes versus that of microglia in this context. WT, Cx3cr1 -deficient and chimeric mice were subjected to a sterile excitotoxic insult via an intrastriatal injection of kainic acid (KA), a conformational analog of glutamate. Following KA administration, circulating monocytes physiologically engrafted the brain and selectively accumulated in the vicinity of excitotoxic lesions where they gave rise to activated macrophages depicting strong Iba1 and CD68 immunoreactivity 7 days post-injury. Monocyte-derived macrophages completely vanished upon recovery and did thus not permanently seed the brain. Furthermore, Cx3cr1 deletion significantly exacerbated neuronal death, behavioral deficits and activation of microglia cells following sterile excitotoxicity. Cx3cr1 disruption also markedly altered the blood levels of patrolling monocytes 24 h after KA administration. The specific elimination of patrolling monocytes using Nr4a1 −/− chimeric mice conditioned with chemotherapy provided direct evidence that these circulating monocytes are essential for neuroprotection. Taken together, these data support a beneficial role of CX3CR1 signaling during excitotoxicity and highlight a novel and pivotal role of patrolling monocytes in neuroprotection. These findings open new research and therapeutic avenues for neuropathological disorders implicating excitotoxicity.

Monocytes can have important effects on the polarization and expansion of lymphocytes and may contribute to shaping primary and memory T‐cell responses in humans and mice. However, their precise contribution in terms of cellular subsets and the molecular mechanisms involved remains to be determined. Mouse monocytes originate from a bone marrow progenitor, the macrophage and DC precursor (MDP), which also gives rise to conventional dendritic cells through a separate differentiation pathway. Mouse monocytes may be grouped in different functional subsets. The CD115+ Gr1+ ‘inflammatory’ monocyte subset can give rise not only to immunostimulatory ‘TipDCs’ in infected mice but also to immunosuppressive ‘myeloid‐derived suppressor cells’ in tumor‐bearing mice. CD115+ Gr1+ monocytes can also contribute to the renewal of several resident subsets of macrophages and DCs, such as microglia and Langerhans cells, in inflammatory conditions. The CD115+ Gr1− ‘resident’ monocyte subset patrols blood vessels in the steady state and extravasates during infection with Listeria monocytogenes or in the healing myocardium. CD115+ Gr1− monocytes are responsible for an early and transient inflammatory burst during Lm infection, which may play a role in the recruitment of other effector cells and subsequently differentiate toward ‘M2’‐like macrophages that may be involved in wound healing. More research will no doubt confirm the existence of more functional subsets, the developmental relationship between mouse subsets as well as the correspondence between mouse subsets and human subsets of monocytes. We will discuss here the potential roles of monocytes in the immune response, the existence of functional subsets and their relationship with other myeloid cells, including dendritic cells.

Background Monocytes are a heterogenous population of immune cells whose subsets and functions become substantially dysregulated with advanced age. Although much of our current understanding of the age-related changes in monocytes is derived from fasting blood samples, most people are predominately in the postprandial state during waking hours. As hormonal, metabolic, and immunological changes in response to the consumption of a meal are manifested in postprandial blood, it’s unclear how age-dependent changes in peripheral monocytes at fasting are impacted by a dietary challenge. Objective We investigated the impact of age and meal consumption on circulating monocyte frequencies and subsets defined as classical (CD14 + CD16-), intermediate (CD14 + CD16 +), or non-classical (CD14dim CD16 +) in a cohort of 349 healthy adult volunteers grouped into categories based on their age: young adults (18–33 y, n  =  123 ), middle adults (34–49 y, n  =  115 ), and older adults (50–66 y, n  =  111 ). Results Following 12-h fast total monocyte counts inversely correlated with subject age. Older adults had significantly fewer circulating monocytes along with elevated levels of TGs, cholesterol, glucose, IL-6, IL-8, TNF, neopterin, and CCL2 compared with young adults. Circulating monocyte pools in older adults consisted of smaller proportions of classical but larger proportions of intermediate and non-classical monocytes. Proportions of classical monocytes were inversely correlated with plasma TNF, IL-8, and neopterin while intermediate monocytes were positively correlated with plasma IL-6, TNF, and neopterin. Three hours after consuming a fat-containing meal postprandial monocyte counts increased in all age groups. Despite age-dependent differences in monocyte subsets at fasting, consumption of a meal induced similar changes in the proportions of classical and non-classical monocytes across age groups. Within the circulating postprandial monocyte pool, percentages of classical monocytes decreased while non-classical monocytes increased. However no change in precursory intermediate monocytes were detected. Our study confirms that ageing is associated with changes in monocyte frequencies and subsets and shows that consuming a fat-containing meal induces temporal changes in monocyte frequency and subsets independently of subject age. Clinical trial Registered on ClincialTrials.gov (Identifier: NCT02367287)

Non-classical monocytes have emerged as the preeminent vascular housekeepers. Continuous intravascular screening is enabled by slow patrolling on the endothelium and allows a rapid response to local perturbations. Intravital imaging has been crucial to elucidate the molecular mechanisms and migratory phenotype of patrolling. In this review, we discuss technical requirements of intravital microscopy such as imaging modalities, labeling strategies, and data analysis. We further focus on patrolling kinetics and adhesion receptors in different organs and vascular beds including arteries during homeostasis and vascular inflammation and define pertinent questions in the field.