Systemic Listeria monocytogenes infection in aged mice induces long-term neuroinflammation: the role of miR-155

Abstract

Abstract Background Understanding mechanisms of pathologic neuroinflammation is essential for improving outcomes after central nervous system infections. Brain tissue-resident memory T cells (bT RM ) are recruited during central nervous system infection and promote pathogen control as well as noxious inflammation. Our prior studies in young mice showed optimal recruitment of CD8 + bT RM during neuroinvasive Listeria monocytogenes ( Lm ) infection required miR-155, and was significantly inhibited by anti-miR-155 oligonucleotides. Since Lm is an important pathogen in the elderly, we hypothesized anti-miR-155 would also inhibit accumulation of CD8 + bT RM in aged mice infected with Lm . Methods Young (2 mo) and aged (> 18 mo) male C57BL/6 mice were infected intra-peritoneally with wild-type Lm , or avirulent Lm mutants lacking the genes required for intracellular motility (Δ actA ) or phagosomal escape (Δ hly ), then were given antibiotics. Brain leukocytes and their intracellular cytokine production were quantified by flow cytometry > 28d post-infection (p.i.). The role of miR-155 was tested by injecting mice with anti-miR-155 or control oligonucleotides along with antibiotics. Results Aged mice had significantly more homeostatic CD8 + bT RM than did young mice, which did not increase after infection with wild-type Lm despite 50% mortality, whereas young mice suffered no mortality after a larger inoculum. For direct comparison of post-infectious neuroinflammation after the same inoculum, young and aged mice were infected with 10 7 CFU Δ actA Lm . This mutant caused no mortality and significantly increased CD8 + bT RM 28d p.i. in both groups, whereas bone marrow-derived myeloid cells, particularly neutrophils, increased only in aged mice. Notably, anti-miR-155 reduced accumulation of brain myeloid cells in aged mice after infection, whereas CD8 + bT RM were unaffected. Conclusions Systemic infection with Lm Δ actA is a novel model for studying infection-induced brain inflammation in aged mice without excessive mortality. CD8 + bT RM increase in both young and aged mice after infection, whereas only in aged mice bone marrow-derived myeloid cells increase long-term. In aged mice, anti-miR-155 inhibits brain accumulation of myeloid cells, but not CD8 + bT RM . These results suggest young and aged mice differ in manifestations and mechanisms of infection-induced neuroinflammation and give insight for developing therapies to ameliorate brain inflammation following severe infection in the elderly.