MicroRNA-21 Limits Macrophage Responses to Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that subverts the innate immune response. The Mtb pandemic is of global concern. Emerging strains of antibiotic-resistant Mtb warrant the development of host-directed therapies and improved vaccination strategies. The macrophage is the primary host cell for Mtb and understanding how the bacterium co-opts this immune cell as a survival niche is of vital importance. Increased glycolysis is an essential process driving host defence against Mtb, but little is known about how metabolism is regulated during infection. MicroRNA-21 (miR-21) is a putative negative regulator of TLR signalling induced to promote immunoregulatory responses, but its role during Mtb infection has not been described.? This work describes a novel role for miR-21 during Mtb infection in the manipulation of metabolic reprogramming.

The findings of this work illustrate that miR-21 is induced by Mtb infection and upregulation of miR-21 coincides with the switch from a pro-inflammatory to an immunoregulatory macrophage permissive to bacterial replication. This overlaps with negative regulation of metabolic reprogramming. Blocking miR-21 increases bacterial containment via increased pro-inflammatory mediators including IL-1. This increase in IL-1 is dependent on enhanced glycolysis, demonstrating that miR-21 negatively regulates immune activation by limiting metabolic reprogramming. This work also describes the mechanism by which miR-21 limits glycolysis, describing a new target at the committed step of glycolysis, namely one isoform of the phosphofructokinase 1 enzyme - PFK-M. Unlike other glycolytic genes and PFK isoforms, PFK-M expression is repressed during Mtb infection. This repression limits glycolysis and pro-inflammatory responses, however an immune activating signal from IFN- can override this brake on immunometabolic reprogramming. IFN- post-transcriptionally limits miR-21 expression, thus relieving the repression of PFK-M and permitting full macrophage activation in response to Mtb. This dual targeting of this pathway by miR-21 and targeting of miR-21 by IFN- highlight the central importance of immunometabolism to the immune response.

By describing a novel level of regulation of the glycolytic machinery by miR-21, modulated by both host & pathogen responses, these findings open new avenues for targeting immunity in infection as well as other diverse diseases including metabolic syndrome & cancer.