High salt reduces the activation of IL-4– and IL-13–stimulated macrophages

Abstract

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.

A salt-sensing kinase in T lymphocytes, SGK1, drives hypertension and hypertensive end-organ damage

“…Salt has also recently been shown to influence antigen-presenting cells such as macrophages. Salt boosts the activation of classical, lipopolysaccharide-induced M1 macrophages and blunts the activation of alternative M2 macrophages (23,24). Zhang et al described a specific activation state of macrophages induced by high salt, which they termed M(Na).…”

Impact of environmental factors on alloimmunity and transplant fate

“…In another study, higher sodium content in the skin enhanced the immune response against the protozoan parasite Leishmania major through stimulation of nuclear factor of activated T cells 5 (NFAT5) in macrophages, promoting activation of classical macrophages that exhibited effector function via NOS2 (6). Lastly, high salt impaired M2 macrophage differentiation through inhibition of mTOR/AKT signaling, resulting in impaired wound healing in mice (7). In sum, increased salt promotes inflammatory macrophages while inhibiting antiinflammatory macrophages (Figure 1).…”

Salt and Pregnancy Complications: A Proposal for Future Research

“…Conversely, a high salt treatment inhibits activities of regulatory T cells and anti-inflammatory cytokines IL-4 and IL-13 [22,23]. High salt treatment also decreases anti-inflammatory cytokines and increases inflammatory cytokines by mouse and human macrophages in vitro [24,25].…”