Palmitate differentially regulates the polarization of differentiating and differentiated macrophages

Abstract

SummaryThe 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-c 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.

Size matters: Effect of granule size of the bone graft substitute (Herafill®) on bone healing using Masquelet's induced membrane in a critical size defect model in the rat's femur

“…Also, evidence is found that high doses of palmitate significantly influence the differentiation of bone marrow‐derived macrophages and promote the anti‐inflammatory M2‐subtype. In already differentiated macrophages, palmitate shows proinflammatory responses (Xiu, Diao, Qi, Catapano, & Jeschke, ).…”

Lipidomic analysis enables prediction of clinical outcomes in burn patients

“…We hypothesize that IL-6 induces preferential mobilization of saturated FFAs over unsaturated lipid species, which are important components in the inflammatory cascade. Alternatively, we recently found that chronic exposure to palmitate induces M2 macrophage differentiation in adipose tissue, which dampens inflammation and facilitates tissue repair27. Therefore, SFAs may in fact contribute to anti-inflammatory activation in select clinical contexts, contrary to its long-established role as a pro-inflammatory lipid species.…”

Impacts of Intralipid on Nanodrug Abraxane Therapy and on the Innate Immune System

“…The oxidations or metabolites of fatty acids promote macrophages differentiating into the M2 subtype 45 , whereas circulating levels of free fatty acids elevate the populations of M1 subtypes 46 . Moreover, chronic treatment with palmitate decreases phagocytosis and inhibits the production of proinflammatory cytokines 47 . In the present study, the in-vitro macrophage differentiation model is established to observe the alternations of macrophages in an Intralipid-containing environment.…”