Monocyte Chemoattractant Protein-1/CC Chemokine Ligand 2 Controls Microtubule-Driven Biogenesis and Leukotriene B4-Synthesizing Function of Macrophage Lipid Bodies Elicited by Innate Immune Response
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Lipid bodies (also known as lipid droplets) are emerging as inflammatory organelles with roles in the innate immune response to infections and inflammatory processes. In this study, we identified MCP-1 as a key endogenous mediator of lipid body biogenesis in infection-driven inflammatory disorders and we described the cellular mechanisms and signaling pathways involved in the ability of MCP-1 to regulate the biogenesis and leukotriene B4 (LTB4) synthetic function of lipid bodies. In vivo assays in MCP-1−/− mice revealed that endogenous MCP-1 produced during polymicrobial infection or LPS-driven inflammatory responses has a critical role on the activation of lipid body-assembling machinery, as well as on empowering enzymatically these newly formed lipid bodies with LTB4 synthetic function within macrophages. MCP-1 triggered directly the rapid biogenesis of distinctive LTB4-synthesizing lipid bodies via CCR2-driven ERK- and PI3K-dependent intracellular signaling in in vitro-stimulated macrophages. Disturbance of microtubule organization by microtubule-active drugs demonstrated that MCP-1-induced lipid body biogenesis also signals through a pathway dependent on microtubular dynamics. Besides biogenic process, microtubules control LTB4-synthesizing function of MCP-1-elicited lipid bodies, in part by regulating the compartmentalization of key proteins, as adipose differentiation-related protein and 5-lipoxygenase. Therefore, infection-elicited MCP-1, besides its known CCR2-driven chemotactic function, appears as a key activator of lipid body biogenic and functional machineries, signaling through a microtubule-dependent manner.
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PI3 kinase inhibition is a known modulator of lipid droplets in mouse macrophages, but this has not been previously shown in human microglia.
“PI3 kinase inhibition is a known modulator of LDs in mouse macrophages26 but this has not been previously shown in human microglia.”
From APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia (2024) · cites this paper as [26]
CCL2 influences lipid droplet biosynthesis and pro-inflammatory polarization, and can interact with other inflammatory mediators.
“CCL2 has been shown to influence LD biosynthesis [71] and pro-inflammatory polarization, and can interact with other inflammatory mediators [72].”
From Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation (2021) · cites this paper as [71]
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Self-citation
- Authors
- Pacheco, P., Vieira-de-Abreu, A., Gomes, R. N., Barbosa-Lima, G., Wermelinger, L. B., Maya-Monteiro, C. M., Silva, A. R., Bozza, M. T., Castro-Faria-Neto, H. C., Bandeira-Melo, C., & Bozza, P. T.
- Affiliations
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz , Rio de Janeiro ,
- Instituto Oswaldo Cruz (BR)
- Universidade Federal do Rio de Janeiro (BR)
- Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro , Rio de Janeiro ,
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-12
- Volume
- 179
- Issue
- 12
- Pages
- 8500-8508
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2158314747
- Cited by
- 103
- References
- 46
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 6 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 2 · 2016: 4 · 2015: 4 · 2014: 6 · 2013: 4 · 2012: 10
- FWCI
- 4.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Arca - Repositório Institucional da Fiocruz (submittedVersion, other-oa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Funders
- Fundação Oswaldo Cruz
- Universidade Federal do Rio de Janeiro
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- MCP-1, lipid droplets, leukotriene B4 synthesis, microtubules, CCR2, ERK signaling, PI3K signaling, 5-lipoxygenase, ADRP, co-infection, lipopolysaccharide, innate immunity
- MeSH terms
- Animals, Chemotaxis, Immunity, Innate, Leukotriene B4, Ligands, Lipopolysaccharides, Macrophages, Mice, Inbred Strains, Microtubules, Sepsis, Chemokine CCL2, Endotoxemia, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinase 1, Lipid Metabolism, Mice, Receptors, CCR2
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