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Macrophages maintain a dynamic balance in physiology. Various known or unknown microenvironmental signals influence the polarization, activation and death of macrophages, which creates an imbalance that leads to disease. Rheumatoid arthritis (RA) is characterized by the massive infiltration of a variety of chronic inflammatory cells in synovia. Abundant activated macrophages found in RA synovia are an early hallmark of RA, and the number of these macrophages can be decreased after effective treatment. In RA, the proportion of M1 (pro-inflammatory macrophages) is higher than that of M2 (anti-inflammatory macrophages). The increased pro-inflammatory ability of macrophages is related to their excessive activation and proliferation as well as an enhanced anti-apoptosis ability. At present, there are no clinical therapies specific to macrophages in RA. Understanding the mechanisms and functional consequences of the heterogeneity of macrophages will aid in confirming their potential role in inflammation development. This review will outline RA-related macrophage properties (focus on polarization, metabolism and apoptosis) as well as the origin of macrophages. The molecular mechanisms that drive macrophage properties also be elucidated to identify novel therapeutic targets for RA and other autoimmune disease., (© 2020 The Authors. Cell Proliferation published by John Wiley & Sons Ltd.)

Inflammatory bowel disease (IBD) is a group of intestinal inflammatory diseases characterized by chronic, recurrent, remitting, or progressive inflammation, which causes the disturbance of the homeostasis between immune cells, such as macrophages, epithelial cells, and microorganisms. Intestinal macrophages (IMs) are the largest population of macrophages in the body, and the abnormal function of IMs is an important cause of IBD. Most IMs come from the replenishment of blood monocytes, while a small part come from embryos and can self-renew. Stimulated by the intestinal inflammatory microenvironment, monocyte-derived IMs can interact with intestinal epithelial cells, intestinal fibroblasts, and intestinal flora, resulting in the increased differentiation of proinflammatory phenotypes and the decreased differentiation of anti-inflammatory phenotypes, releasing a large number of proinflammatory factors and aggravating intestinal inflammation. Based on this mechanism, inhibiting the secretion of IMs' proinflammatory factors and enhancing the differentiation of anti-inflammatory phenotypes can help alleviate intestinal inflammation and promote tissue repair. At present, the clinical medication of IBD mainly includes 5-aminosalicylic acids (5-ASAs), glucocorticoid, immunosuppressants, and TNF-α inhibitors. The general principle of treatment is to control acute attacks, alleviate the condition, reduce recurrence, and prevent complications. Most classical IBD therapies affecting IMs function in a variety of ways, such as inhibiting the inflammatory signaling pathways and inducing IM2-type macrophage differentiation. This review explores the current understanding of the involvement of IMs in the pathogenesis of IBD and their prospects as therapeutic targets. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease with a complex etiology. Monocyte-derived macrophages (MDMs) infiltration are associated with RA severity. We have reported the deletion of G-protein-coupled receptor kinase 2 (GRK2) reprograms macrophages toward an anti-inflammatory phenotype by recovering G-protein-coupled receptor signaling. However, as more GRK2-interacting proteins were discovered, the GRK2 interactome mechanisms in RA have been understudied. Thus, in the collagen-induced arthritis mouse model, we performed genetic GRK2 deletion using GRK2 f/f Lyz2 -Cre+/− mice. Synovial inflammation and M1 polarization were improved in GRK2 f/f Lyz2 -Cre+/− mice. Supporting experiments with RNA-seq and dual-luciferase reporter assays identified peroxisome proliferator-activated receptor γ (PPAR γ) as a new GRK2-interacting protein. We further confirmed that fms-related tyrosine kinase 1 (Flt-1), which promoted macrophage migration to induce angiogenesis, was inhibited by GRK2-PPAR γ signaling. Mechanistically, excess GRK2 membrane recruitment in CIA MDMs reduced the activation of PPAR γ ligand-binding domain and enhanced Flt-1 transcription. Furthermore, the treatment of mice with GRK2 activity inhibitor resulted in significantly diminished CIA pathology, Flt-1+ macrophages induced-synovial inflammation, and angiogenesis. Altogether, we anticipate to facilitate the elucidation of previously unappreciated details of GRK2-specific intracellular signaling. Targeting GRK2 activity is a viable strategy to inhibit MDMs infiltration, affording a distinct way to control joint inflammation and angiogenesis of RA. The recruitment of GRK2 to the membrane inhibits PPAR γ -Tyr473 activation, consequently leading to synovial Flt-1+ macrophages infiltration, ultimately aggravating synovial inflammation and angiogenesis in rheumatoid arthritis. [Display omitted] [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is characterized by the massive infiltration of various chronic inflammatory cells in synovia. In synovial fluid of patients with RA, M1 macrophages are dominant among all subtypes of macrophages, the mechanisms of macrophages polarization imbalance in RA has not been fully illuminated. The prostaglandin E2 (PGE2) augments M2 polarization in part via the cyclic adenosine monophosphate (cAMP)-cyclic AMP responsive element binding (CREB) signaling. However, previous study found constant stimulus of PGE2 on fibroblast-like synovial cells of adjuvant arthritis rats induced the decrease of cAMP, which is primarily caused by G protein-coupled receptor kinase 2 (GRK2)-induced EP4 over- desensitization. Whether GRK2 mediated-EP4 over-desensitization reduces the level of cAMP and inhibits M2 polarization in RA is unclear. Here we observed M1 macrophages were dominant in peritoneal macrophages (PMs), bone-marrow-derived macrophages (BMMs) and synovial macrophages of collagen-induced arthritis (CIA) mice. PGE2 stimulated M2 polarization via the EP4-cAMP-CREB in normal mice, while failed to promote M2 polarization in the PMs of CIA mice. Further, we found the EP4 over-desensitization stimulated by PGE2 induced abnormal PGE2-cAMP-CREB signaling as well as the imbalance of macrophage polarization. Targeted disruption of GRK2 in Raw264.7 (RAW) through GRK2 siRNA or CRISPR/Cas9 downregulated the M1 macrophage markers, upregulated the M2 macrophage markers and the EP4 membrane localization. The reduced M1/M2 ratio and increased p-CREB expression were observed in BMMs and PMs of GRK2+/− mice. This study highlighted a novel role of GRK2 in regulating macrophages function in RA and provided new idea for precision treatment of RA. [ABSTRACT FROM AUTHOR]

Nanoplastics have attracted significant attention due to their harmful effects on the environment and organisms. However, accurately detecting and quantifying nanoplastics that are ingested by organisms poses a challenge. Conventional organic fluorescent-labeled nanoplastics have reduced labeling efficiency due to aggregation-caused quenching (ACQ), leading to artifacts caused by leakage of fluorescent molecules. To address these limitations, this study utilized AIE fluorescence for internally labeling polystyrene nanoparticles. AIE-active molecules do not emit fluorescence in dilute solutions, thus preventing accuracy issues associated with fluorescence leakage. Three model plastics (TPE@PS) of varying particle sizes were synthesized via the swelling method. The preparation parameters were optimized, followed by stability tests conducted on TPE@PS. Fluorescence microscopy imaging revealed significant uptake of TPE@PS by RAW246.7 cells. A successful standard curve of fluorescence intensity-concentration was established successfully and utilized to accurately quantify the amount of TPE@PS that was ingested by RAW246.7 cells. The results indicate a consistent increase with increasing concentration in TPE@PS uptake across all particle sizes during the fixed exposure duration of 48 h. Furthermore, RAW264.7 cells exhibited a higher propensity to uptake smaller TPE@PS particles. Flow cytometry was also employed to validated the suitability of TPE@PS as a model nanoplastic for tracing purposes. • AIE-labeled nanoplastics (TPE@PS) overcome drawbacks of conventional dyes. • TPE@PS accurately quantifies cellular uptake with minimal misclassification. • Fluorescence and flow cytometry experiments demonstrate a high level of agreement. • TPE@PS could clarify the pathways through which organisms internalise nanoplastics. [ABSTRACT FROM AUTHOR]