Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling

Abstract

Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germline loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder. We show that loss-of-function of SLC29A3 activates nucleoside-sensing Toll-like receptors and downstream MEK-ERK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation.

Rheumatological complaints in H syndrome: from inflammatory profiling to target treatment in a case study

“…Moreover, the deletion of SLC29A3 in preclinical studies is associated with impaired autophagic regulation and altered proliferative potential in stem cells, which may account for some of the syndromic features described in H syndrome [ 12 ]. In addition, according to recent research, the defective function of ENT3, leading to accumulation of adenosine in lysosomes, could lead to abnormal stimulation of TLR7 and TLR8, resulting in MAPK signaling and activation of an inflammatory response driven by IFNs [ 9 , 10 , 18 ]. Of note, HCQ is a weak base that accumulates in the lysosomes of immune cells, where it exerts its action by interacting with membrane stability, inhibiting the proteolytic processing of TLR7 and thereby its activation [ 19 – 21 ].In this, HCQ may target quite directly the underlying molecular pathway involved in inflammation in H syndrome, providing hope for individuals suffering from this rare disorder.…”

“…Recent data suggest that an alternative strategy may rely in targeting MAPK with MEK inhibitor therapy, which led to resolution of histiocytosis and inflammation in a patient with H syndrome [ 18 ].…”

Kombo knife combined with sorafenib in liver cancer treatment: Efficacy and safety under immune function influence

“…One study confirmed that the upregulation of SLC29A3 promotes the proliferation, invasion, and migration of pancreatic cancer cells and is associated with poor prognosis[ 41 ]. Another study revealed that SLC29A3 affects cytokine secretion and the inflammatory response by regulating the TLR-MAPK signaling pathway[ 42 ]. These studies provide important experimental and clinical evidence, thus confirming the critical role of PPIA and SLC29A3 in immune regulation and offering insights for a deeper understanding of the underlying mechanisms by which PPIA and SLC29A3 function in HCC.…”