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Abstract
The activation of M1 macrophages can be achieved by stimulating them with lipopolysaccharide (LPS) and interferon-γ (IFN-γ). However, M1 can be found under physiological conditions without any pathological stimuli. This study aimed to understand the involvement of RANKL-induced M1 macrophages in bone formation compared with pathologically induced macrophages. Fischer rats were used to investigate macrophage distribution in normal and injured femoral condyles in vivo. Bone marrow-derived macrophages (BMDMs) were activated with LPS+IFN-γ and RANKL to achieve M1 activation in vitro. Gene expression related to inflammation, osteoclastogenesis, angiogenesis, and migration was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and fluorescence-activated cell sorting (FACS). Tissue macrophages showed distinct expression patterns at different bone regions. RANKL was found in close proximity to inducible nitric oxide synthase-positive (iNOS+) cells in vivo, suggesting an association between RANKL expression and iNOS+ cells, especially in trabecular bone. RANKL-induced macrophages showed a different cytokine secretion profile compared with pathologically induced macrophages. Both osteoclasts and M1 macrophages peaked on day 7 during bone healing. RANKL could trigger M1-like macrophages with properties that were different from those of LPS+IFN-γ-induced macrophages. These RANKL-activated M1 macrophages were actively involved in bone formation.
Highlights
Macrophages are a heterogeneous population of hematopoietic origin that are involved in crucial innate immune defense and have tissue-specific functions in the regulation and maintenance of organ homeostasis
cluster of differentiation 68 (CD68) is a marker for the macrophage lineage, including monocytes, macrophages, giant cells, and osteoclasts.[17] inducible nitric oxide synthase (iNOS) and chemokine receptor type 7 (CCR7) are markers for M1 macrophages, whereas Arginase[1] and cluster of differentiation 163 (CD163) are markers for M2 macrophages.[18,19]
Cells labeled by the antibodies against iNOS, CCR7, Arginase[1], and CD163 shared similar expression patterns with regular cell morphology (Figure 1c–f)
Summary
Macrophages are a heterogeneous population of hematopoietic origin that are involved in crucial innate immune defense and have tissue-specific functions in the regulation and maintenance of organ homeostasis. Tissue macrophages are identified in many tissues and have two key functions: (1) to respond to pathogens and modulate the adaptive immune responses and (2) to facilitate tissue repair and regeneration.[1,2] As heterogeneous cells with great plasticity, macrophages activated by interferon-γ (IFN-γ), and lipopolysaccharide (LPS) achieve a “classically activated” or a “killer” phenotype (CAM, M1) characterized by high level secretion of pro-inflammatory cytokines and the production of reactive nitrogen and oxygen intermediates. Extending this idea to tissue macrophages has gained increased interest in recent years because these unique phenotypes likely reflect the different functions and influence of the tissue environment in which they reside.[6]
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