| Summary: | Macrophage activation, first generalized to the M1/M2 dichotomy, is a complex and central process of the innate immune response. Simply, M1 describes the classical proinflammatory activation, leading to tissue damage, and M2 the alternative activation promoting tissue repair. Given the central role of macrophages in multiple diseases, the ability to noninvasively differentiate between M1 and M2 activation states would be highly valuable for monitoring disease progression and therapeutic responses. Since M1/M2 activation patterns are associated with differential metabolic reprogramming, we hypothesized that hyperpolarized <sup>13</sup>C magnetic resonance spectroscopy (HP <sup>13</sup>C MRS), an innovative metabolic imaging approach, could distinguish between macrophage activation states noninvasively. The metabolic conversions of HP [1-<sup>13</sup>C]pyruvate to HP [1-<sup>13</sup>C]lactate, and HP [1-<sup>13</sup>C]dehydroascorbic acid to HP [1-<sup>13</sup>C]ascorbic acid were monitored in live M1 and M2 activated J774a.1 macrophages noninvasively by HP <sup>13</sup>C MRS on a 1.47 Tesla NMR system. Our results show that both metabolic conversions were significantly increased in M1 macrophages compared to M2 and nonactivated cells. Biochemical assays and high resolution <sup>1</sup>H MRS were also performed to investigate the underlying changes in enzymatic activities and metabolite levels linked to M1/M2 activation. Altogether, our results demonstrate the potential of HP <sup>13</sup>C MRS for monitoring macrophage activation states noninvasively.
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