title: Palmitate differentially regulates the polarization of differentiating and differentiated macrophages.
abstract: The tissue accumulation of M1 macrophages in patients with metabolic diseases such as obesity and type 2 diabetes mellitus has been well-documented. Interestingly, it is an accumulation of M2 macrophages that is observed in the adipose, liver and lung tissues, as well as in the circulation, of patients who have had major traumas such as a burn injury or sepsis; however, the trigger for the M2 polarization observed in these patients has not yet been identified. In the current study, we explored the effects of chronic palmitate and high glucose treatment on macrophage differentiation and function in murine bone-marrow-derived macrophages. We found that chronic treatment with palmitate decreased phagocytosis and HLA-DR expression in addition to inhibiting the production of pro-inflammatory cytokines. Chronic palmitate treatment of bone marrows also led to M2 polarization, which correlated with the activation of the peroxisome proliferator-activated receptor-γ signalling pathway. Furthermore, we found that chronic palmitate treatment increased the expression of multiple endoplasmic reticulum (ER) stress markers, including binding immunoglobulin protein. Preconditioning with the universal ER stress inhibitor 4-phenylbutyrate attenuated ER stress signalling and neutralized the effect of palmitate, inducing a pro-inflammatory phenotype. We confirmed these results in differentiating human macrophages, showing an anti-inflammatory response to chronic palmitate exposure. Though alone it did not promote M2 polarization, hyperglycaemia exacerbated the effects of palmitate. These findings suggest that the dominant accumulation of M2 in adipose tissue and liver in patients with critical illness may be a result of hyperlipidaemia and hyperglycaemia, both components of the hypermetabolism observed in critically ill patients.
authors.affiliation: Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.
authors.forename: Fangming
authors.initials: F
authors.lastname: Xiu
authors.affiliation: Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.
authors.forename: Li
authors.initials: L
authors.lastname: Diao
authors.affiliation: Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Qi
authors.affiliation: Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Catapano
authors.affiliation: Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.|Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.|Division of Plastic Surgery, Department of Surgery, Department of Immunology, University of Toronto, Toronto, ON, Canada.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Jeschke
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000494:pharmacology; D015798:HLA-DR1 Antigen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D015798:HLA-DR1 Antigen; D018836:Inflammation Mediators; D047495:PPAR gamma; D019308:Palmitic Acid; D005947:Glucose
keywords: bone marrow; endoplasmic reticulum stress; free fatty acids; macrophage; palmitate