Abstract
Signalling is of particular importance in immune cells, and upstream in the signalling pathway many membrane receptors are functional only as complexes, co-locating with particular lipid species. Work over the last 15 years has shown that plasma membrane lipid composition is close to a critical point of phase separation, with evidence that cells adapt their composition in ways that alter the proximity to this thermodynamic point. Macrophage cells are a key component of the innate immune system, are responsive to infections and regulate the local state of inflammation. We investigate changes in the plasma membrane’s proximity to the critical point as a response to stimulation by various pro- and anti-inflammatory agents. Pro-inflammatory (interferon γ, Kdo 2-Lipid A, lipopolysaccharide) perturbations induce an increase in the transition temperature of giant plasma membrane vesicles; anti-inflammatory interleukin 4 has the opposite effect. These changes recapitulate complex plasma membrane composition changes, and are consistent with lipid criticality playing a master regulatory role: being closer to critical conditions increases membrane protein activity.
Highlights
Macrophages are extremely versatile cells of the innate immune system that are able to activate and adapt their functionality depending on the specific milieu [1]
interferon γ (IFN-γ) is a cytokine mainly produced by natural killer (NK) and T helper 1 (Th1) cells; signalling from the IFN-γ receptor (IFNGR) controls the regulation of specific genes related to the production of cytokine receptors, cell activation markers and adhesion molecules [1]
The biological question addressed here concerns macrophage cells, which we conditioned via pro- and anti-inflammatory stimuli, before extracting Giant plasma membrane vesicles (GPMVs) and measuring their phase transition temperatures
Summary
Macrophages are extremely versatile cells of the innate immune system that are able to activate and adapt their functionality depending on the specific milieu [1]. Following phagocytosis of material resulting from trauma, or pathogens, or detection of specific functional molecules, macrophages can change their gene regulatory state and polarize into activated states, where, for example, they produce immune effector molecules such as cytokines for intercellular communication [2,3,4]. The stimuli that promote M1 macrophage activation are mainly interferon γ (IFN-γ), lipopolysaccharides (LPSs) and granulocyte–macrophage colony-stimulating factor (GM-CSF). IFN-γ is a cytokine mainly produced by natural killer (NK) and T helper 1 (Th1) cells; signalling from the IFN-γ receptor (IFNGR) controls the regulation of specific genes related to the production of cytokine receptors, cell activation markers and adhesion molecules [1].
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