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The R1441C-LRRK2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner

ABSTRACT: Considering age is the greatest risk factor for many neurodegenerative diseases, aging, in particular aging of the immune system, is the most underappreciated and understudied contributing factor in the neurodegeneration field. Genetic variation around the LRRK2 gene affects risk of both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein has been implicated in peripheral immune signaling, however, the effects of an aging immune system on LRRK2 function have been neglected to be considered. We demonstrate here that the R1441C mutation induces a hyper-responsive phenotype in macrophages from young female mice, characterized by increased effector functions, including stimulation-dependent antigen presentation, cytokine release, phagocytosis, and lysosomal function. This is followed by age-acquired immune cell exhaustion in a Lrrk2-kinase-dependent manner. Immune-exhausted macrophages exhibit suppressed antigen presentation and hypophagocytosis, which is also demonstrated in myeloid cells from R1441C and Y1699C-PD patients. Our novel findings that LRRK2 mutations confer immunological advantage at a young age but may predispose the carrier to age-acquired immune exhaustion have significant implications for LRRK2 biology and therapeutic development. Indeed, LRRK2 has become an appealing target in PD, but our findings suggest that more research is required to understand the cell-type specific consequences and optimal timing of LRRK2-targeting therapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE246691 | GEO | 2024/01/31

REPOSITORIES: GEO

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Project description:Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can also promote improved survival for some cancers3-5 and enhance responses to some immune checkpoint blockade therapies6-8. The role of the immune system in the obesity-cancer connection and how obesity influences immunotherapy, however, remain unclear. While PD-1 expression by macrophages has been described9-12, we found that obesity selectively induced PD-1 on macrophages and that PD-1 directly impaired macrophage function. Single cell RNA sequencing of murine colorectal carcinoma tumors showed obesity remodeled myeloid and T cell populations, with fewer clonally expanded effector T cells and increased abundance of PD-1+ tumor-associated macrophages (TAM). Cytokines and molecules associated with obesity, including IL-6, leptin, and insulin, and the unsaturated fatty acid palmitate, induced PD-1 expression on macrophages in a glycolysis-dependent manner and that MTORC1 pathway signaling is essential for PD1 expression. PD-1+ TAMs had increased mitochondrial respiration, fatty acid metabolism and cell cylewhile PD-1- TAMs had increased inflammatory signature , phagocytosis and antigen presentation to T cells. These patterns were directly regulated by PD-1, as recombinant PD-L1 reduced macrophage glycolysis, phagocytic capacity and antigen presentation, and this was reversed with blocking PD-1 antibody. Further, inhibition of glycolysis with 2-deoxyglucose prevented the increase in CD86, MHC-I and MHC-II that would otherwise occur with anti-PD-1 treatment. Conversely, PD-1-deficient Pdcd1-/- TAMs had high rates of glycolysis, phagocytosis, and expression of MHC-II. Myeloid-specific PD-1 deficiency correlated with slower tumor growth, enhanced TAM antigen presentation capability, and increased CD8 T cell activation together with reduced markers of exhaustion. These findings show metabolic signaling and type 1 inflammatory cues in obesity induces PD-1-mediated suppression of TAM function and reveal a unique macrophage-specific and glycolysis-dependent mechanism to modulate immune tumor surveillance and checkpoint blockade. This may contribute to increased cancer risk yet improved response to PD-1 blockade in TAM-enriched tumors and obesity.

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The R1441C-LRRK2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner

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