IFNs exert both protective and detrimental effects on the host during intracellular bacterial infection. IFNγ is known to induce T-helper (Th)1 responses, and to activate and enhance the expression of antibactericidal molecules in phagocytes to kill intracellular bacteria.
21,23 In RPE cells, both type I and type II IFN are known to inhibit cytomegalovirus (CMV) and
Toxoplasma gondii replication, which involves indoleamine 2,3 dioxygenase (IDO)-induced tryptophan depletion.
24,25 IDO-1 was also one of the IFN-induced genes we found in
Mtb-infected RPE. Possibly IDO-induced tryptophan depletion inhibits
Mtb replication in RPE, but this would require further study.
26 In contrast, excessive IFNα/β signaling has been linked to high
Mtb disease activity in patients with clinical disease.
18,19 Suppression of cytokines crucial for host defense against
Mtb, including IL-1α, IL-1β, IL-12, and TNFα, and also repression of innate cell responsiveness to IFNγ, have been proposed as important mechanisms of IFNα/β-mediated immunosuppression during
Mtb infection.
4,20,21,27–31 Moreover, RPE-derived IFNβ can downregulate CXCL9 and intercellular adhesion molecule 1 (ICAM-1) expression by RPE in an autocrine manner. This potentially limits retinal T-lymphocyte/natural killer (NK) cell recruitment and has been proposed as an immunosuppressive mechanism that protects the retina from excessive inflammation, for instance, in the case of RPE infection.
20 Our data suggest that in RPE cells, at least during the early stages of
Mtb infection, IFN signaling may have a beneficial effect by inhibiting the outgrowth of intracellular
Mtb. However, it could be speculated that the (prolonged) high induction of IFNα/β could potentially be detrimental at later stages of infection and thereby contributes to
Mtb-mediated uveitis due to chronic infection or
Mtb latency in the RPE cells. Clearly, unraveling the exact role or balance of IFN signaling and Th1 induction in RPE in
Mtb-mediated uveitis requires further investigation.