Sterile alpha and HEAT/Armadillo motif-containing protein 1 (SARM1) is a member of the Toll/IL-1R (TIR) domain protein family with a role in innate immunity and neuronal cell death. A major recent discovery was that the TIR domain of SARM1 has NADaseenzymatic activity, and that this activity is required for SARM1-dependent axon degeneration in neurons and mediating innate immune responses in lower organism. We have reported that SARM1 is also a regulator of inflammasome responses in murine macrophages, however, the function of SARM1 in human macrophages and monocytes is still unclear. The aim of this study was to determine the role of SARM1 in human monocytes. To do this we generated both loss-of-function and gain-of-function cell models: SARM1 deficient BLaER1 monocytes and THP-1 cells stably expressing either SARM1 wild-type or NADase-dead E642A point-mutant proteins. Following LPS stimulation in these cell models, we found TNFalpha induction was increased in the absence of SARM1, and suppressed by gain of SARM1 expression in monocytes. SARM1-dependent TNFalpha modulation is likely due to negative regulation of TRIF signalling by SARM1. Also, although lack of SARM1 in BLaER1 cells did not significantly affect inflammasome responses, gain of SARM1 in THP-1 did lead to robust inhibition of IL-1beta secretion, consistent with previous results from mouse cells. Interestingly, SARM1 E642A-mutant also inhibited IL-1beta secretion suggesting that the NADase activity is not required for inflammasome regulation. Further, This phenomenon was also observed in mouse NLRP3 inflammasome reconstitution assay, suggesting NADaseactivity of SARM1 is not required to mediate immune responses in mammalian cells. This study reveals that SARM1 can regulate proinflammatory cytokine responses in human monocytes, further emphasising an immune role for SARM1 beyond axonal degeneration.

Clarifying the role of human SARM1, and its NADase activity, in monocytes

Exploring the intricacies of host-pathogen communication is vital in order to understand why
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