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This study demonstrates that TRPM7, a channel-kinase protein, plays a critical role in regulating pathogenic TH17 cells that drive autoimmune diseases like multiple sclerosis. Researchers found elevated TRPM7 activity in immune cells from MS patients and showed that mice with disrupted TRPM7 kinase activity had impaired pathogenic TH17 cell differentiation, reduced migration to the central nervous system, and milder experimental autoimmune encephalomyelitis. The TRPM7 kinase disruption also increased regulatory T cells while decreasing pathogenic TH17 infiltration through effects on cell migration and intestinal reactivation.
Why it matters
This research identifies TRPM7 kinase as a potential therapeutic target for multiple sclerosis and other autoimmune diseases, with the advantage of suppressing disease-causing TH17 cells while preserving beneficial regulatory T cells. Targeting this specific kinase could lead to more selective immunotherapies with fewer side effects than current broad immunosuppressive treatments.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
The melastatin-like transient receptor potential channel, TRPM7, is crucial for signaling in leukocytes. It harbors a channel domain, permeable to divalent cations as well as a serine/threonine -kinase, phosphorylating inter alia SMAD2. TRPM7 kinase activity is essential for the differentiation of non-pathogenic T helper 17 (TH17) cells as well as for T cell colonization and alloreactivity in the gut. As pathogenic TH17 (pTH17) cells drive autoimmune diseases, we studied TRPM7 kinase involvement in pTH17 polarization and function as well as in the development of multiple sclerosis (MS), using human T cells and established murine experimental autoimmune encephalomyelitis (EAE) models. Our results reveal an elevated TRPM7 activity in T effector cells derived from the cerebrospinal fluid (CSF) of MS patients, in line with higher functional TRPM7 expression on human TH17 cells. Utilizing a mouse line with disrupted kinase activity (Trpm7R/R), we uncovered both impaired differentiation of pathogenic TH17 cells as well as a significantly milder course of TH17-mediated transfer EAE in Trpm7R/R mice compared to Trpm7+/+ controls. In the CNS of Trpm7R/R mice, the number of FOXP3+ T cells (Tregs) was increased, while fewer TH17 cells infiltrated the CNS due to a migration defect of transferred pTH17 cells in the Trpm7R/R hosts and a failure to reactivate in the intestine, due to reduced MHCII signaling. Thus, inactivation of TRPM7 kinase may represent a promising therapeutic strategy targeting both differentiation and reactivation of pTH17 cells while preserving Tregs function and thereby dampening CNS inflammation in MS.
Source: Pathogenicity of autoreactive TH17 cells is modulated by the TRPM7 kinase