TRPM7 Kinase Is Essential for Neutrophil Recruitment and Function via Regulation of Akt/mTOR Signaling

Abstract

During inflammation, neutrophils are one of the first responding cells of innate immunity, contributing to a fast clearance of infection and return to homeostasis. However, excessive neutrophil infiltration accelerates unsolicited disproportionate inflammation for instance in autoimmune diseases such as rheumatoid arthritis. The transient-receptor-potential channel-kinase TRPM7 is an essential regulator of immune system homeostasis. Naïve murine T cells with genetic inactivation of the TRPM7 enzyme, due to a point mutation at the active site, are unable to differentiate into pro-inflammatory T cells, whereas regulatory T cells develop normally. Moreover, TRPM7 is vital for lipopolysaccharides (LPS)-induced activation of murine macrophages. Within this study, we show that the channel-kinase TRPM7 is functionally expressed in neutrophils and has an important impact on neutrophil recruitment during inflammation. We find that human neutrophils cannot transmigrate along a CXCL8 chemokine gradient or produce reactive oxygen species in response to gram-negative bacterial lipopolysaccharide LPS, if TRPM7 channel or kinase activity are blocked. Using a recently identified TRPM7 kinase inhibitor, TG100-115, as well as murine neutrophils with genetic ablation of the kinase activity, we confirm the importance of both TRPM7 channel and kinase function in murine neutrophil transmigration and unravel that TRPM7 kinase affects Akt1/mTOR signaling thereby regulating neutrophil transmigration and effector function. Hence, TRPM7 represents an interesting potential target to treat unwanted excessive neutrophil invasion.

TRPM7 channel inhibition attenuates rheumatoid arthritis articular chondrocyte ferroptosis by suppression of the PKCα-NOX4 axis

“…TRPM7 activation leads to neuron death via mediating Ca 2+ overload and ROS production, with suppression of TRPM7 significantly reducing oxidative damage [ 43 , 44 ]. Further, the channel-kinase of TRPM7 is functionally expressed in neutrophils, playing an essential role in neutrophil recruitment during inflammation [ 45 ]. Our previous study found that blockade of TRPM7 had a protective effect on RA articular cartilage destruction [ 20 ].…”

LncRNA HOTAIR sponges miR-301a-3p to promote glioblastoma proliferation and invasion through upregulating FOSL1

“…TRPM7 is a bifunctional protein fusing a divalent cations channel to a C-terminal serine/threonine kinase. Since cloned two decades ago, TRPM7 has emerged as new therapeutic target and is associated with tumor progression, anoxic neuronal death, tissue fibrosis, giant platelet disorders, neutrophil recruitment, and production of reactive oxygen species [ 30 , 31 ]. Our group has long been focusing on the study of TRPM7’s potential as a therapeutic target in glioblastoma.…”

Immunomodulatory functions of TRPM7 and its implications in autoimmune diseases

“…In addition to the TRPM7 channel, a recent study reported a role for TRPM7 kinase in neutrophil migration [84]. Using the kinase inhibitor TG100-115, chemotaxis of neutrophils towards CXCL8 was significantly attenuated, possibly through the Akt/ mTOR signalling pathway [84]. This opens new doors for study of the function of TRPM7 kinase.…”

“…Calcium flicker was shown to regulate fibroblast migration, and this may also be key to the regulation of neutrophil migration by TRPM7, but more research is needed to establish these results. In addition to the TRPM7 channel, a recent study reported a role for TRPM7 kinase in neutrophil migration [84]. Using the kinase inhibitor TG100-115, chemotaxis of neutrophils towards CXCL8 was significantly attenuated, possibly through the Akt/ mTOR signalling pathway [84].…”