High salt reduces the activation of IL-4- and IL-13-stimulated macrophages.
A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL-4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt-induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis.
Katrina J
KJ
Binger
Matthias
M
Gebhardt
Matthias
M
Heinig
Carola
C
Rintisch
Agnes
A
Schroeder
Wolfgang
W
Neuhofer
Karl
K
Hilgers
Arndt
A
Manzel
Christian
C
Schwartz
Markus
M
Kleinewietfeld
Jakob
J
Voelkl
Valentin
V
Schatz
Ralf A
RA
Linker
Florian
F
Lang
David
D
Voehringer
Mark D
MD
Wright
Norbert
N
Hubner
Ralf
R
Dechend
Jonathan
J
Jantsch
Jens
J
Titze
Dominik N
DN
Müller
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D002478:Cells, Cultured; D002686:Chitin / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D042421:Histone Code / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000145:classification / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D012965:Sodium Chloride / Q000494:pharmacology*; D017673:Sodium Chloride, Dietary / Q000494:pharmacology / Q000633:toxicity*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D014945:Wound Healing / Q000187:drug effects
D018793:Interleukin-13; D017673:Sodium Chloride, Dietary; D002686:Chitin; D015847:Interleukin-4; D012965:Sodium Chloride; C546843:mTOR protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases