Macrophage Krüppel-like factor 4 regulates response to Mycobacterium tuberculosis infection

Kruppel-like factor 4 (KLF4) is a transcription factor that polarizes macrophages towards an anti-inflammatory (M2) phenotype, which suggests that it may regulate immune responses to Mycobacterium tuberculosis (Mtb), as immune evasion by Mtb may be due to an overabundance of anti-inflammatory mediators in response to infection. We hypothesize that myeloid KLF4 is permissive of immune evasion by Mtb, causing decreased control of Mtb infection. There are no prior in vivo data on the role of KLF4 in infection. Using mice with myeloid-specific knockout of KLF4 (LysM Cre/Cre KLF4 fl/fl , abbreviated Mye-KO) we observed decreased Mtb CFU in macrophage cultures in vitro and in lungs of Mye-KO mice early in infection (day 14) relative to wild-type controls. However, these experiments also revealed complexities to the KLF4-Mtb relationship. Despite their improved control of early infection, at later time points Mye-KO mice developed worsened clinical disease features, such as wasting, which suggests that the loss of KLF4 results in pathologic immune state. In addition, we found discrepancy between KLF4 RNA and protein expression during Mtb infection, suggesting that KLF4 is regulated at a posttranslational level during infection. We are designing an in vitro system in which to study the molecular mechanisms of KLF4 regulation and activity in macrophages. Our data indicate that KLF4 plays an important role is regulating immune responses to Mtb with the potential to both diminish host defense mechanisms and repress host-damaging immune mechanisms.