Impairment of systemic DHA synthesis affects macrophage plasticity and polarization: implications for DHA supplementation during inflammation

Emanuela Talamonti,Abolfazl Asadi,Alexander W Fischer,Anna M Pauter,Anders Jacobsson,Valerio Chiurchiù

doi:10.1007/s00018-017-2498-9

Abstract

Docosahexaenoic acid (DHA) is an omega-3 fatty acid obtained from the diet or synthesized from alpha-linolenic acid through the action of fatty acid elongases (ELOVL) and desaturases. DHA plays important roles in the central nervous system as well as in peripheral organs and is the precursor of several molecules that regulate resolution of inflammation. In the present study, we questioned whether impaired synthesis of DHA affected macrophage plasticity and polarization both in vitro and in vivo models. For this we investigated the activation status and inflammatory response of bone marrow-derived M1 and M2 macrophages obtained from mice deficient of Elovl2 (Elovl2−/−), a key enzyme for DHA synthesis in mammals. Although both wild type and Elovl2−/− mice were able to generate efficient M1 and M2 macrophages, M1 cells derived from Elovl2−/− mice showed an increased expression of key markers (iNOS, CD86 and MARCO) and cytokines (IL-6, IL-12 and IL-23). However, M2 macrophages exhibited upregulated M1-like markers like CD80, CD86 and IL-6, concomitantly with a downregulation of their signature marker CD206. These effects were counteracted in cells obtained from DHA-supplemented animals. Finally, white adipose tissue of Elovl2−/− mice presented an M1-like pro-inflammatory phenotype. Hence, impairment of systemic DHA synthesis delineates an alteration of M1/M2 macrophages both in vitro and in vivo, with M1 being hyperactive and more pro-inflammatory while M2 less protective, supporting the view that DHA has a key role in controlling the balance between pro- and anti-inflammatory processes.

Highlights

Docosahexaenoic acid (DHA) is an ω-3 fatty acid prerequisite for normal growth, development, and function in mammals
As already shown by our previous studies where total serum DHA levels were drastically reduced in Elovl2−/− mice [4, 5] and given the important role of DHA in inflammatory responses, we examined whether the impairment of systemic DHA synthesis could modulate the immunophenotype of bone marrow-derived M1 and M2 macrophages obtained from WT and Elovl2−/− mice (Fig. 1)
Which are required for SPMs production from EPA and DHA, our results showed a reduced expression of 5-LOX, 12-LOX and 15-LOX, which was significant only for 12-LOX, in M1 macrophages of Elovl2−/− mice compared to WT mice

Summary

Introduction

Docosahexaenoic acid (DHA) is an ω-3 fatty acid prerequisite for normal growth, development, and function in mammals. It cannot be synthesized de novo and, as such, has to be derived from diet or synthesized from dietary α-linolenic acid (ALA) through a series of elongation and desaturation steps performed by distinct enzymes residing in the endoplasmic reticulum [1]. ELOVL2, involved in the elongation of C22 PUFA, is significantly expressed in liver, testis, uterus, placenta, mammary gland, retina, adipose tissue, and certain areas of the brain, all of which are tissues that are documented as being rich in DHA [2, 3].

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