Chloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseases

Abstract

For over a half-century the anti-malarial drug chloroquine (CQ) has been used as a therapeutic agent, alone or in combination, to treat autoimmune diseases. However, neither the underlying mechanism(s) of action nor their molecular target(s) are well defined. The orphan nuclear receptor Nurr1 (also known as NR4A2) is an essential transcription factor affecting the development and maintenance of midbrain dopaminergic neurons. In this study, using in vitro T cell differentiation models, we demonstrate that CQ activates TREG cell differentiation and induces Foxp3 gene expression in a Nurr1-dependent manner. Remarkably, CQ appears to induce Nurr1 function by two distinct mechanisms: firstly, by direct binding to Nurr1’s ligand-binding domain and promoting its transcriptional activity and secondly by upregulation of Nurr1 expression through the CREB signaling pathway. In contrast, CQ suppressed gene expression and differentiation of pathogenic TH17 cells. Importantly, using a valid animal model of inflammatory bowel disease (IBD), we demonstrated that CQ promotes Foxp3 expression and differentiation of TREG cells in a Nurr1-dependent manner, leading to significant improvement of IBD-related symptoms. Taken together, these data suggest that CQ ameliorates autoimmune diseases via regulating Nurr1 function/expression and that Nurr1 is a promising target for developing effective therapeutics of human inflammatory autoimmune diseases.

Comprehensive Analysis of the Immune and Stromal Compartments of the CNS in EAE Mice Reveal Pathways by Which Chloroquine Suppresses Neuroinflammation

“…Additionally, CQ directly modulates DCs by inducing iNOS and pSTAT1 expression, and the lack of these molecules abrogated the tolerogenic phenotype of CQ-treated DCs [ 30 , 32 ]. A similar increase in Foxp3 + Treg cells in models of inflammatory bowel disease and lupus was observed [ 53 , 54 ]. CQ directly induced Foxp3 expression in T cells in a Nurr1-dependent manner [ 53 ].…”

“…A similar increase in Foxp3 + Treg cells in models of inflammatory bowel disease and lupus was observed [ 53 , 54 ]. CQ directly induced Foxp3 expression in T cells in a Nurr1-dependent manner [ 53 ]. Thus, the literature data show that CQ induces STAT1 in DCs, T-bet in Th17 cells and Nurr1 in naïve T cells [ 32 , 53 , 54 ].…”

Caspase1/11 signaling affects muscle regeneration and recovery following ischemia, and can be modulated by chloroquine

“…9 Ischemia, CQ absence of caspase-1/11signaling alter oxidative metabolism in muscle stellate cells (MuSC). Seahorse™ analysis of maximal respiration, spare respiratory capacity (including %), non-mitochondrial oxygen consumption, ATP production, and coupling efficiency in MuSC harvested from tibialis anterior (TA) of nonischemic and ischemic limbs of C57Bl6/J (WT) and caspase1/11KO mice at 21 days after femoral artery ligation (FAL) treated with either PBS or CQ (50 mg/kg); * p < 0.05, **p < 0.01, ***p < 0.001 replacement and fibrosis may result from inflammation, and since CQ is known to be anti-inflammatory (Park et al 2019) we hypothesized that CQ would reduce inflammatory markers, including those associated with inflammasome signaling, such as caspase-1. Instead, we found that CQ increased caspase-1 expression, cleavage and activity in C2C12 mouse myoblasts without increasing cell death (Xu et al 2018).…”

Caspase1/11 signaling affects muscle regeneration and recovery following ischemia, and can be modulated by chloroquine

“…Fat replacement and brosis may result from in ammation, and since CQ is known to be antiin ammatory (46) we hypothesized that CQ would reduce in ammatory markers, including those associated with in ammasome signaling, such as caspase-1. Instead, we found that CQ increased caspase-1 expression, cleavage and activity in C2C12 mouse myoblasts without increasing cell death (2).…”