impact of L-Arginine transportation on myeloid-derived suppressor cell function
Inflammatory chronic prostatitis/chronic pelvic pain syndrome has been linked to autoimmune inflammation. Likewise, prostatitis has been linked to prostate cancer development and progression. A better understanding of the mechanisms by which inflammation is regulated may provide the foundation for novel approaches to controlling inflammation. Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells that expand during benign and cancer-associated inflammation. MDSC are characterized by their ability to potently inhibit T cell responses. Therefore, by dampening inflammation, MDSC benefit autoimmune diseases. Instead, they aggravate cancer by blocking antitumor immune responses. Identification of mechanisms underlying MDSC activities can enable the development of strategies to modify MDSC function in disease. Thus, in this study we investigated the mechanisms that regulate MDSC functions. Using murine models of prostatitis and cancer, we identified two novel pathways, p38 and p53 signaling, that are involved in MDSC functional activity and differentiation capacity, respectively. We showed that p38-MAPK pathway is involved in the regulation of MDSC-mediated immunoregulatory processes such that inhibition of p38 diminished MDSC expansion at the inflamed prostate, leading to greater numbers of T cells. Furthermore, inhibition of p38 reduced Nos2 expression and abolished MDSC suppressor activity. Our studies also demonstrated that the in vitro differentiation capacity of MDSC is restricted to cells at the peripheral sites. Tumor site monocytic-MDSC lacked the ability to differentiate into other cells types such as osteoclasts and granulocytic-MDSC, whereas the bone marrow and spleen counterparts could form both cell types. Notably, we identified p53 as a critical regulator of MDSC differentiation. Induction of p53 signaling elevated the differentiation of the bone marrow MDSC into granulocytic cell types. A well-established mechanism for MDSC suppressive activity is the metabolism of L-Arginine (L-Arg) by Arginase 1 (ARG1) and nitric oxide synthase 2 (NOS2). Therefore, we hypothesized that restricting MDSC uptake of L-Arg is a critical control point to modulate their suppressor activity. To this end, we have identified the mechanisms by which extracellular L-Arg is transported into MDSC. We have shown that cationic amino acid transporter 2 (Cat2) expression is induced in MDSC at the inflammatory sites in parallel to Arg1 and Nos2 expression. CAT2 acts as an important regulator of MDSC suppressive function. MDSC that lack CAT2 have reduced capacity to suppress T cell responses both ex vivo and in vivo, as evidenced by increased T cell expansion in prostatitis and decreased tumor growth in cancer models. The abrogation of suppressive function is due to low intracellular L-Arginine levels, which leads to the impaired ability of NOS2 to catalyze L-Arginine metabolic processes. In summary, here we identify 3 components that regulate MDSC: L-Arg transportation through CAT2, p38-MAPK signaling and p53 signaling. CAT2 and p38 are critical regulators of MDSC suppressive function and p53 acts as an inducer of MDSC differentiation. Targeting of these molecules can be utilized as a strategy to modulate MDSC function in disease.
Ratliff, Purdue University.
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