This mini-review summarizes the current evidence for the role of macrophage activation and polarization in inflammation and immune response pertinent to interstitial lung disease, specifically pulmonary fibrosis. In the fibrosing lung, the production and function of inflammatory and fibrogenic mediators involved in the disease development have been reported to be regulated by the effects of polarized M1/M2 macrophage populations. The M1 and M2 macrophage phenotypes were suggested to correspond with the pro-inflammatory and pro-fibrogenic signatures, respectively. These responses towards tissue injury followed by the development and progression of lung fibrosis are further regulated by macrophage-derived microRNAs (miRNAs). Besides cellular miRNAs, extracellular exosomal-miRNAs derived from M2 macrophages have also been proposed to promote the progression of pulmonary fibrosis. In a future perspective, harnessing the noncoding miRNAs with a key role in the macrophage polarization is, therefore, suggested as a promising therapeutic strategy for this debilitating disease.

• Klíčová slova
• M1/M2 polarization, MicroRNAs, exosomes, macrophage plasticity, pulmonary fibrosis,
• MeSH
• aktivace makrofágů genetika   imunologie   MeSH
• biologické markery MeSH
• biologické modely MeSH
• cytokiny metabolismus   MeSH
• exozómy metabolismus   MeSH
• lidé MeSH
• makrofágy imunologie   metabolismus   MeSH
• mediátory zánětu metabolismus   MeSH
• mikro RNA genetika   MeSH
• náchylnost k nemoci * MeSH
• plasticita buňky MeSH
• plicní fibróza etiologie   metabolismus   patologie   MeSH
• regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• biologické markery MeSH
• cytokiny MeSH
• mediátory zánětu MeSH
• mikro RNA MeSH

With the introduction of a new interdisciplinary field, osteoimmunology, today, it is well acknowledged that biomaterial-induced inflammation is modulated by immune cells, primarily macrophages, and can be controlled by nanotopographical cues. Recent studies have investigated the effect of surface properties in modulating the immune reaction, and literature data indicate that various surface cues can dictate both the immune response and bone tissue repair. In this context, the purpose of the present study was to investigate the effects of titanium dioxide nanotube (TNT) interspacing on the response of the macrophage-like cell line RAW 264.7. The cells were maintained in contact with the surfaces of flat titanium (Ti) and anodic TNTs with an intertube spacing of 20 nm (TNT20) and 80 nm (TNT80), under standard or pro-inflammatory conditions. The results revealed that nanotube interspacing can influence macrophage response in terms of cell survival and proliferation, cellular morphology and polarization, cytokine/chemokine expression, and foreign body reaction. While the nanostructured topography did not tune the macrophages' differentiation into osteoclasts, this behavior was significantly reduced as compared to flat Ti surface. Overall, this study provides a new insight into how nanotubes' morphological features, particularly intertube spacing, could affect macrophage behavior.

• Klíčová slova
• TiO2 nanotubes, cytokines, inflammation, intertube spacing, macrophage, osteoclastogenesis,
• MeSH
• makrofágy metabolismus   MeSH
• nanotrubičky * MeSH
• povrchové vlastnosti MeSH
• titan * metabolismus   farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• titan * MeSH
• titanium dioxide MeSH Prohlížeč

PURPOSE OF REVIEW: Joint replacement has revolutionized the treatment of end-stage arthritis. We highlight the key role of macrophages in the innate immune system in helping to ensure that the prosthesis-host interface remains biologically robust. RECENT FINDINGS: Osteoimmunology is of great interest to researchers investigating the fundamental biological and material aspects of joint replacement. Constant communication between cells of the monocyte/macrophage/osteoclast lineage and the mesenchymal stem cell-osteoblast lineage determines whether a durable prosthesis-implant interface is obtained, or whether implant loosening occurs. Tissue and circulating monocytes/macrophages provide local surveillance of stimuli such as the presence of byproducts of wear and can quickly polarize to pro- and anti-inflammatory phenotypes to re-establish tissue homeostasis. When these mechanisms fail, periprosthetic osteolysis results in progressive bone loss and painful failure of mechanical fixation. Immune modulation of the periprosthetic microenvironment is a potential intervention to facilitate long-term durability of prosthetic interfaces.

• Klíčová slova
• Inflammation, Innate immune system, Joint replacement, Macrophage, Osteoimmunology, Periprosthetic osteolysis, Prosthesis,
• MeSH
• artroplastiky kloubů * MeSH
• lidé MeSH
• makrofágy MeSH
• osteolýza * MeSH
• protézy kloubů * MeSH
• selhání protézy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH

• Klíčová slova
• NAFLD (non alcoholic fatty liver disease), OXPHOS (oxidative phosphorylation), amino acid metabolism, immunometabolism, lipid metabolism, macrophage,
• MeSH
• játra * metabolismus   MeSH
• lidé MeSH
• makrofágy metabolismus   MeSH
• zánět * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• úvodníky MeSH

Monocytes arriving at the site of infection differentiate into functional effector macrophages to replenish the resident sentinel cells. Bordetella pertussis, the pertussis agent, secretes an adenylate cyclase toxin-hemolysin (CyaA) that binds myeloid phagocytes through complement receptor 3 (CD11b/CD18) and swiftly delivers its adenylyl cyclase enzyme domain into phagocytes. This ablates the bactericidal capacities of phagocytes through massive and unregulated conversion of cytosolic ATP into the key signaling molecule cAMP. We show that exposure of primary human monocytes to as low a concentration as 22.5 pM CyaA, or a low (2:1) multiplicity of infection by CyaA-producing B. pertussis bacteria, blocks macrophage colony-stimulating factor (M-CSF)-driven differentiation of monocytes. CyaA-induced cAMP signaling mediated through the activity of protein kinase A (PKA) efficiently blocked expression of macrophage markers, and the monocytes exposed to 22.5 pM CyaA failed to acquire the characteristic intracellular complexity of mature macrophage cells. Neither M-CSF-induced endoplasmic reticulum (ER) expansion nor accumulation of Golgi bodies, mitochondria, or lysosomes was observed in toxin-exposed monocytes, which remained small and poorly phagocytic and lacked pseudopodia. Exposure to 22.5 pM CyaA toxin provoked loss of macrophage marker expression on in vitro differentiated macrophages, as well as on primary human alveolar macrophages, which appeared to dedifferentiate into monocyte-like cells with upregulated CD14 levels. This is the first report that terminally differentiated tissue-resident macrophage cells can be dedifferentiated in vitro The results suggest that blocking of monocyte-to-macrophage transition and/or dedifferentiation of the sentinel cells of innate immunity through cAMP-elevating toxin action may represent a novel immune evasion strategy of bacterial pathogens.IMPORTANCE Macrophages are key sentinel cells of the immune system, and, as such, they are targeted by the toxins produced by the pertussis agent Bordetella pertussis The adenylate cyclase toxin (CyaA) mediates immune evasion of B. pertussis by suspending the bactericidal activities of myeloid phagocytes. We reveal a novel mechanism of potential subversion of host immunity, where CyaA at very low (22 pM) concentrations could inhibit maturation of human monocyte precursors into the more phagocytic macrophage cells. Furthermore, exposure to low CyaA amounts has been shown to trigger dedifferentiation of mature primary human alveolar macrophages back into monocyte-like cells. This unprecedented capacity is likely to promote survival of the pathogen in the airways, both by preventing maturation of monocytes attracted to the site of infection into phagocytic macrophages and by dedifferentiation of the already airway-resident sentinel cells.

• Klíčová slova
• Bordetella, adenylate cyclase toxin, cyclic AMP, dedifferentiation, macrophage,
• MeSH
• adenylátcyklasový toxin škodlivé účinky   metabolismus   MeSH
• alveolární makrofágy účinky léků   metabolismus   MeSH
• Bordetella pertussis chemie   MeSH
• buněčná diferenciace účinky léků   MeSH
• interakce hostitele a patogenu MeSH
• lidé MeSH
• monocyty účinky léků   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenylátcyklasový toxin MeSH

PURPOSE: Intracranial aneurysm (IA) rupture results in one of the most severe forms of stroke, with severe neurological sequelae. Inflammation appears to drive aneurysm formation and progression with macrophages playing a key role in this process. However, less is known about their involvement in aneurysm rupture. This study is aimed at demonstrating how relationship between the M1 (pro-inflammatory) and M2 (reparative) macrophage subtypes affect an aneurysm's structure resulting in its rupture. METHODS: Forty-one saccular aneurysm wall samples were collected during surgery including 13 ruptured and 28 unruptured aneurysm sacs. Structural changes were evaluated using histological staining. Macrophages in the aneurysm wall were quantified and defined as M1 and M2 using HLA-DR and CD163 antibodies. Aneurysm samples were divided into four groups according to the structural changes and the M2/1 ratio. Data were analyzed using the Mann-Whitney U test. RESULTS: This study has demonstrated an association between the severity of structural changes of an aneurysm with inflammatory cell infiltration within its wall and subsequent aneurysm rupture. More severe morphological changes and a significantly higher number of inflammatory cells were observed in ruptured IAs (p < 0.001). There was a prevalence of M2 macrophage subtypes within the wall of ruptured aneurysms (p < 0.001). A subgroup of unruptured IAs with morphological and inflammatory changes similar to ruptured IAs was observed. The common feature of this subgroup was the presence of an intraluminal thrombus. CONCLUSIONS: The degree of inflammatory cell infiltration associated with a shift in macrophage phenotype towards M2 macrophages could play an important role in structural changes of the aneurysm wall leading to its rupture.

• Klíčová slova
• Brain aneurysm, Inflammation, Intracranial aneurysm, Macrophage polarization, Subarachnoid hemorrhage,
• MeSH
• intrakraniální aneurysma * komplikace   patologie   MeSH
• lidé MeSH
• makrofágy * patologie   MeSH
• prasklé aneurysma * komplikace   patologie   MeSH
• trombóza komplikace   MeSH
• zánět komplikace   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION: Inhalation of nanomaterials may induce inflammation in the lung which if left unresolved can manifest in pulmonary fibrosis. In these processes, alveolar macrophages have an essential role and timely modulation of the macrophage phenotype is imperative in the onset and resolution of inflammatory responses. This study aimed to investigate, the immunomodulating properties of two industrially relevant high aspect ratio nanomaterials, namely nanocellulose and multiwalled carbon nanotubes (MWCNT), in an alveolar macrophage model. METHODS: MH-S alveolar macrophages were exposed at air-liquid interface to cellulose nanocrystals (CNC), cellulose nanofibers (CNF) and two MWCNT (NM-400 and NM-401). Following exposure, changes in macrophage polarization markers and secretion of inflammatory cytokines were analyzed. Furthermore, the potential contribution of epigenetic regulation in nanomaterial-induced macrophage polarization was investigated by assessing changes in epigenetic regulatory enzymes, miRNAs, and rRNA modifications. RESULTS: Our data illustrate that the investigated nanomaterials trigger phenotypic changes in alveolar macrophages, where CNF exposure leads to enhanced M1 phenotype and MWCNT promotes M2 phenotype. Furthermore, MWCNT exposure induced more prominent epigenetic regulatory events with changes in the expression of histone modification and DNA methylation enzymes as well as in miRNA transcript levels. MWCNT-enhanced changes in the macrophage phenotype were correlated with prominent downregulation of the histone methyltransferases Kmt2a and Smyd5 and histone deacetylases Hdac4, Hdac9 and Sirt1 indicating that both histone methylation and acetylation events may be critical in the Th2 responses to MWCNT. Furthermore, MWCNT as well as CNF exposure led to altered miRNA levels, where miR-155-5p, miR-16-1-3p, miR-25-3p, and miR-27a-5p were significantly regulated by both materials. PANTHER pathway analysis of the identified miRNA targets showed that both materials affected growth factor (PDGF, EGF and FGF), Ras/MAPKs, CCKR, GnRH-R, integrin, and endothelin signaling pathways. These pathways are important in inflammation or in the activation, polarization, migration, and regulation of phagocytic capacity of macrophages. In addition, pathways involved in interleukin, WNT and TGFB signaling were highly enriched following MWCNT exposure. CONCLUSION: Together, these data support the importance of macrophage phenotypic changes in the onset and resolution of inflammation and identify epigenetic patterns in macrophages which may be critical in nanomaterial-induced inflammation and fibrosis.

• Klíčová slova
• epigenetic, fibrosis, inflammation, macrophage, miRNA, nanomaterials, polarization,
• MeSH
• celulosa metabolismus   MeSH
• epigeneze genetická MeSH
• lidé MeSH
• makrofágy metabolismus   MeSH
• mikro RNA * genetika   metabolismus   MeSH
• nanotrubičky uhlíkové * toxicita   chemie   MeSH
• zánět metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• celulosa MeSH
• mikro RNA * MeSH
• nanotrubičky uhlíkové * MeSH

If misregulated, macrophage (Mϕ)-T cell interactions can drive chronic inflammation thereby causing diseases, such as rheumatoid arthritis (RA). We report that in a proinflammatory environment, granulocyte-Mϕ (GM-CSF)- and Mϕ colony-stimulating factor (M-CSF)-dependent Mϕs have dichotomous effects on T cell activity. While GM-CSF-dependent Mϕs show a highly stimulatory activity typical for M1 Mϕs, M-CSF-dependent Mϕs, marked by folate receptor β (FRβ), adopt an immunosuppressive M2 phenotype. We find the latter to be caused by the purinergic pathway that directs release of extracellular ATP and its conversion to immunosuppressive adenosine by co-expressed CD39 and CD73. Since we observed a misbalance between immunosuppressive and immunostimulatory Mϕs in human and murine arthritic joints, we devised a new strategy for RA treatment based on targeted delivery of a novel methotrexate (MTX) formulation to the immunosuppressive FRβ+CD39+CD73+ Mϕs, which boosts adenosine production and curtails the dominance of proinflammatory Mϕs. In contrast to untargeted MTX, this approach leads to potent alleviation of inflammation in the murine arthritis model. In conclusion, we define the Mϕ extracellular purine metabolism as a novel checkpoint in Mϕ cell fate decision-making and an attractive target to control pathological Mϕs in immune-mediated diseases.

• Klíčová slova
• adenosine, chronic inflammation, macrophage polarization, macrophage-T cell interaction, methotrexate, purine metabolism, rheumatoid arthritis,
• MeSH
• adenosin imunologie   MeSH
• buněčná diferenciace * MeSH
• faktor stimulující granulocyto-makrofágové kolonie farmakologie   MeSH
• faktor stimulující kolonie makrofágů farmakologie   MeSH
• imunosupresiva aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• makrofágy imunologie   metabolismus   MeSH
• methotrexát aplikace a dávkování   terapeutické užití   MeSH
• modely nemocí na zvířatech MeSH
• monocyty účinky léků   MeSH
• myši MeSH
• proliferace buněk MeSH
• puriny metabolismus   MeSH
• revmatoidní artritida farmakoterapie   imunologie   MeSH
• synoviální tekutina cytologie   imunologie   MeSH
• zánět farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosin MeSH
• faktor stimulující granulocyto-makrofágové kolonie MeSH
• faktor stimulující kolonie makrofágů MeSH
• imunosupresiva MeSH
• methotrexát MeSH
• puriny MeSH

The immunoreactivity or/and stress response can be induced by nanomaterials' different properties, such as size, shape, etc. These effects are, however, not yet fully understood. This study aimed to clarify the effects of SiO2 nanofibers (SiO2NFs) on the cellular responses of THP-1-derived macrophage-like cells. The effects of SiO2NFs with different lengths on reactive oxygen species (ROS) and pro-inflammatory cytokines TNF-α and IL-1β in THP-1 cells were evaluated. From the two tested lengths, it was only the L-SiO2NFs with a length ≈ 44 ± 22 µm that could induce ROS. Compared to this, only S-SiO2NFs with a length ≈ 14 ± 17 µm could enhance TNF-α and IL-1β expression. Our results suggested that L-SiO2NFs disassembled by THP-1 cells produced ROS and that the inflammatory reaction was induced by the uptake of S-SiO2NFs by THP-1 cells. The F-actin staining results indicated that SiO2NFs induced cell motility and phagocytosis. There was no difference in cytotoxicity between L- and S-SiO2NFs. However, our results suggested that the lengths of SiO2NFs induced different cellular responses.

• Klíčová slova
• SiO2 nanofibers, THP-1-derived macrophage-like cells, cytotoxicity, immunoreactivity,
• MeSH
• cytokiny metabolismus   MeSH
• lidé MeSH
• makrofágy MeSH
• oxid křemičitý * farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• THP-1 buňky MeSH
• TNF-alfa * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytokiny MeSH
• oxid křemičitý * MeSH
• reaktivní formy kyslíku MeSH
• TNF-alfa * MeSH

The immune response is an energy-demanding process that must be coordinated with systemic metabolic changes redirecting nutrients from stores to the immune system. Although this interplay is fundamental for the function of the immune system, the underlying mechanisms remain elusive. Our data show that the pro-inflammatory polarization of Drosophila macrophages is coupled to the production of the insulin antagonist ImpL2 through the activity of the transcription factor HIF1α. ImpL2 production, reflecting nutritional demands of activated macrophages, subsequently impairs insulin signaling in the fat body, thereby triggering FOXO-driven mobilization of lipoproteins. This metabolic adaptation is fundamental for the function of the immune system and an individual's resistance to infection. We demonstrated that analogically to Drosophila, mammalian immune-activated macrophages produce ImpL2 homolog IGFBP7 in a HIF1α-dependent manner and that enhanced IGFBP7 production by these cells induces mobilization of lipoproteins from hepatocytes. Hence, the production of ImpL2/IGFBP7 by macrophages represents an evolutionarily conserved mechanism by which macrophages alleviate insulin signaling in the central metabolic organ to secure nutrients necessary for their function upon bacterial infection.

• Klíčová slova
• Drosophila, ImpL2, insulin resistance, lipoproteins, macrophage polarization,
• MeSH
• antagonisté inzulinu metabolismus   farmakologie   MeSH
• bakteriální infekce * metabolismus   MeSH
• Drosophila metabolismus   MeSH
• inzulin metabolismus   MeSH
• inzulinová rezistence * MeSH
• makrofágy metabolismus   MeSH
• proteiny Drosophily * metabolismus   MeSH
• proteiny vázající insulinu podobné růstové faktory metabolismus   MeSH
• savci MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antagonisté inzulinu MeSH
• ImpL2 protein, Drosophila MeSH Prohlížeč
• inzulin MeSH
• proteiny Drosophily * MeSH
• proteiny vázající insulinu podobné růstové faktory MeSH