Tuberculosis (TB) remains one of the world deadliest diseases. TB infection causes significant inflammation, often inducing irreversible tissue damage. New options to control TB-associated inflammation are urgently required. This study examined if regulating the expression of Tristetraprolin (TTP) could aid control of this inflammation. TTP inhibits pro-inflammatory responses by degrading target mRNAs including TNF and IL-1b. TTP is active when unphosphorylated but it often remains inactive inside the body. To keep TTP in its active form, murine serines at positions 52 and 178 in TTP were replaced by non-phosphorylatable alanine residues (TTPaa). Macrophages from TTPaa mice displayed a reduced pro-inflammatory response when infected with Mycobacterium tuberculosis (M. tb) while maintaining control of infection. TTPaa mice were then infected with M. tb. Infection was accompanied by an early reduction in inflammatory cells recruited to the lungs of the TTPaa mice, though this was then followed by a transient increase in inflammatory cells and bacterial growth in the lungs. Similarly to in vitro analysis, lung cells from TTPaa mice showed a decrease in secretion of pro-inflammatory cytokines and chemokines, but this was not accompanied by sustained reduction in inflammation and granuloma formation. While the presence of TTP in a permanently active form reduced early inflammation, it did not prevent mice from activating T cells, recruiting inflammatory cells to form granulomas and eventually controlling bacterial growth in an equivalent manner to wild-type mice. These data suggest that other pathways might compensate for the effects of active TTP, limiting the capacity of this modification to permanently reduce M.tbinduced inflammation.