Macrophage is a kind of immune cell and performs multiple functions including pathogen phagocytosis, antigen presentation and tissue remodeling. To fulfill their functionally distinct roles, macrophages undergo polarization towards a spectrum of phenotypes, particularly the classically activated (M1) and alternatively activated (M2) subtypes. However, the binary M1/M2 phenotype fails to capture the complexity of macrophages subpopulations in vivo. Hence, it is crucial to employ spatiotemporal imaging techniques to visualize macrophage phenotypes and polarization, enabling the monitoring of disease progression and assessment of therapeutic responses to drug candidates. This review begins by discussing the origin, function and diversity of macrophage under physiological and pathological conditions. Subsequently, we summarize the identified macrophage phenotypes and their specific biomarkers. In addition, we present the imaging probes locating the lesions by visualizing macrophages with specific phenotype in vivo. Finally, we discuss the challenges and prospects associated with monitoring immune microenvironment and disease progression through imaging of macrophage phenotypes.

Alcohol-associated liver disease (ALD) is a condition that develops due to prolonged and excessive alcohol consumption. It encompasses various stages of liver damage, including fatty liver, alcoholic hepatitis, and cirrhosis. Immune cells, particularly macrophages, of various types play a significant role in the onset and progression of the disease. Macrophages observed in the liver exhibit diverse differentiation forms, and perform a range of functions. Beyond M1 and M2 macrophages, human macrophages can polarize into distinct phenotypes in response to various stimuli. Recent advancements have improved our understanding of macrophage diversity and their role in the progression of ALD. This mini-review provides a concise overview of the latest findings on the role and differentiation of macrophages in ALD. Additionally, it discusses potential therapeutic targets associated with macrophages and explores potential therapeutic strategies.

The heart is a muscular organ that pumps blood throughout the body and is one of the most vital organs in human body. While cardiomyocytes are essential for maintaining the normal function of the heart, a variety of cardiovascular diseases such as coronary artery occlusion, arrhythmia, and myocarditis can lead to cardiomyocyte death, resulting in deterioration of heart function. The adult mammalian heart is incapable of regenerating sufficient cardiomyocytes following cardiac injuries, eventually leading to heart failure and death. Cardiac macrophages are ubiquitously distributed in the healthy heart and accumulated at the site of injury. Macrophages play essential roles in regulating homeostasis and proliferation of cardiomyocyte, promoting electrical conduction, and removing dead cardiomyocytes and debris through direct and indirect cell-cell crosstalk. In this review, we summarize the latest insights into the role of macrophages in maintaining cardiac homeostasis and the macrophage-cardiomyocyte crosstalk in both healthy and injured scenarios. Video Abstract.

Macrophage performs multiple functions such as pathogen phagocytosis, antigen presentation, and tissue remodeling by polarizing toward a spectrum of phenotypes. Dynamic imaging of macrophage phenotypes is critical for evaluating disease progression and the therapeutic response of drug candidates. However, current technologies cannot identify macrophage phenotypes in vivo. Herein, a surface-enhanced Raman scattering nanoprobe, AH1, which enables the accurate determination of physiological pH with high sensitivity and tissue penetration depth through ratiometric Raman signals is developed. Due to the phenotype-dependent metabolic reprogramming, AH1 can effectively identify macrophage subpopulations by measuring the acidity levels in phagosomes. After intravenous administration, AH1 not only visualizes the spatial distribution of macrophage phenotypes in brain tumors and epileptic regions of mouse models, but also reveals the repolarization of macrophages in brain lesions after drug intervention. This work provides a new tool for dynamically monitoring the disease-associated immune microenvironment and evaluating the efficacy of immune-therapeutics in vivo.

Respiratory syncytial virus (RSV) is the most common cause of viral bronchiolitis among children worldwide, yet there is no vaccine for RSV disease. This study investigates the potential of cube and sphere-shaped cerium oxide nanoparticles (CNP) to modulate reactive oxygen (ROS) and nitrogen (RNS) species and immune cell phenotypes in the presence of RSV infection in vitro and in vivo. Cube and sphere-shaped CNP were synthesized by hydrothermal and ultrasonication methods, respectively. Physico-chemical characterization confirmed the shape of sphere and cube CNP and effect of various parameters on their particle size distribution and zeta potential. In vitro results revealed that sphere and cube CNP differentially modulated ROS and RNS levels in J774 macrophages. Specifically, cube CNP significantly reduced RSV-induced ROS levels without affecting RNS levels while sphere CNP increased RSV-induced RNS levels with minimal effect on ROS levels. Cube CNP drove an M1 phenotype in RSV-infected macrophages in vitro by increasing macrophage surface expression of CD80 and CD86 with a concomitant increase in TNFα and IL-12p70, while simultaneously decreasing M2 CD206 expression. Intranasal administration of sphere and cube-CNP were well-tolerated with no observed toxicity in BALB/c mice. Notably, cube CNP preferentially accumulated in murine alveolar macrophages and induced their activation, avoiding enhanced uptake and activation of other inflammatory cells such as neutrophils, which are associated with RSV-mediated inflammation. In conclusion, we report that sphere and cube CNP modulate macrophage polarization and innate cellular responses during RSV infection.

Cardiac fibrosis is a key feature of hypertensive cardiac remodeling. In response to microenvironmental stimuli, phenotypic and functional changes in macrophages are considered important determinants of cardiac fibrosis attenuation. VO-OHpic, a phosphatase and tension homolog of chromosome 10 (PTEN) inhibitor, has been demonstrated to be cardioprotective in cardiac remodeling. However, whether VO-OHpic can improve cardiac fibrosis and macrophage polarization remains elusive. The interaction between VO-OHpic and the macrophage phenotype to attenuate cardiac fibrosis was studied in both spontaneously hypertensive rats in vivo and an Ang II-induced hypertension model in vitro. In vitro experiments showed that VO-OHpic promoted M2 macrophage polarization and markedly inhibited proinflammatory M1 macrophages, while VO-OHpic treatment of protein kinase B (AKT)-knockdown/LY294002 (a PI3K inhibitor) macrophages exerted a reduced effect. In a coculture system, culturing cardiac fibroblasts with VO-OHpic-treated macrophages led to significant suppression of proliferation, fibrotic marker expression, and transforming growth factor (TGF)-β and Smad 2/3 protein expression. Taken together, VO-OHpic mediated a fibro-protective effect and increased M2 macrophage polarization via the phosphatidylinositol 3-kinase (PI3K)/AKT/TGF-β/Smad2/3 pathway.

Of central importance to tissue engineering and drug delivery is identifying polymer parameters that increase or decrease specific cytokines in response to biomaterials. In this study, we have interrogated the effects of material descriptors and material characteristics on pro-inflammatory, pro-angiogenic, and naïve macrophages using polymeric particles (∼600 nm), functionalized with 13 different moieties. We characterized tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) secretion for the three macrophage populations and used the quantitative structure-activity relationship method (QSAR) to accurately predict cytokine secretion for the different macrophage phenotypes. The findings presented here demonstrate that altering cellular responses to polymers can be achieved through exploiting material parameters. For pro-inflammatory macrophages, polarity and the ability to hydrogen bond appear to significantly impact TNF-α secretion while charge impacted pro-angiogenic macrophages. Naïve cells were impacted by charge in a similar manner as the pro-angiogenic cells; however, hydrophilicity also increased TNF-α secretion in these cells. For IL-10 secretion, hydrogen bonding was very negatively correlated with pro-inflammatory cells, whereas it was positively correlated with pro-angiogenic cells.

Macrophages are key players in the progression of many diseases, ranging from rheumatoid arthritis to cancer. Drug delivery systems have the potential not only to transport payloads to diseased tissue but also to influence cell behavior. Here, poly(N-isopropylacrylamide-co-acrylic acid) (pNIPAm-co-AAc) microparticles were modified with 14 different arginine derivatives. These particles were then incubated with interleukin-4 or lipopolysaccharide-stimulated macrophages or naïve macrophages (RAW 264.7). The phenotypic state of the macrophages was assessed by measuring arginase activity, tumor necrosis factor-α (TNF-α) secretion, and nitrite production. Partial least-squares analysis revealed material properties and descriptors that shifted the macrophage phenotype for the three cell conditions in this study. Material descriptors relating to secondary bonding were suggested to play a role in shifting phenotypes in all three macrophage culture conditions. These findings suggest that macrophage responses could be altered through drug delivery vehicles, and this method could be employed to assist in screening potential candidates.

Titanium surface mediated immunomodulation may address compromised post-implantation bone healing in diabetes mellitus. To assess in vitro phenotypic changes, M1 and M2 polarised Type 2 diabetic rat (Goto Kakizaki, GK) macrophages were cultured on micro-rough (SLA) or hydrophilic nanostructured SLA (modSLA) titanium. The in vivo effects of the SLA and modSLA surfaces on macrophage phenotype, wound-associated protein expression and bone formation were investigated using a critical-sized calvarial defect model. Compared to healthy macrophages, GK M2 macrophage function was compromised, secreting significantly lower levels of the anti-inflammatory cytokine IL-10. The modSLA surface attenuated the pro-inflammatory cellular environment, reducing pro-inflammatory cytokine production and promoting M2 macrophage phenotype differentiation. ModSLA also suppressed gene expression associated with macrophage multinucleation and giant cell formation and stimulated pro-osteogenic genes in co-cultured osteoblasts. In vivo, modSLA enhanced osteogenesis compared to SLA in GK rats. During early healing, proteomic analysis of both surface adherent and wound exudate material showed that modSLA promoted an immunomodulatory pro-reparative environment. The modSLA surface therefore successfully compensated for the compromised M2 macrophage function in Type 2 diabetes by attenuating the pro-inflammatory response and promoting M2 macrophage activity, thus restoring macrophage homeostasis and resulting in a cellular environment favourable for enhanced osseous healing.

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