Lactoferrin reduces mycobacterial M1-type inflammation induced with trehalose 6,6′-dimycolate and facilitates the entry of fluoroquinolone into granulomas

Abstract

Primary Mycobacterium tuberculosis (Mtb) infection results in the formation of a densely packed granulomatous response that essentially limits entry and efficacy of immune effector cells. Furthermore, the physical nature of the granuloma does not readily permit entry of therapeutic agents to sites where organisms reside. The Mtb cell wall mycolic acid, trehalose 6,6’-dimycolate (TDM), is a physiologically-relevant molecule to model macrophage mediated events during establishment of the tuberculosis-induced granuloma pathogenesis. No current therapeutic modalities focus to modulate host immune responses to ameliorate tuberculosis disease. Previous studies identified lactoferrin (LF), a natural iron-binding protein proven to modulate inflammation, as able to ameliorate granuloma cohesiveness. Therefore, a series of studies were enabled to further examine the effect of recombinant human LF (rHLF) on histological progression of the TDM-induced pathology. Treatment with rHLF demonstrated significant reduction in size and number of inflammatory foci following TDM injection, with reduced pulmonary pro-inflammatory cytokines TNF-α and IL-1β. LF allowed greater penetration of fluoroquinolone therapeutic to sites of pathology; TDM alone treated mice demonstrated exclusion of ofloxacin to regions of inflammatory response, whereas rHLF treated animals demonstrated increased penetration to responding foci. Finally, recent findings support the hypothesis that this mycobacterial mycolic acid can specifically recruit M1-like polarized macrophages; rHLF treatment was shown to limit the level of this M1-like phenotypic recruitment, corresponding highly with the occurrence of the decreased inflammatory response.

Antibacterial properties of lactoferrin: A bibliometric analysis from 2000 to early 2022

“…Therefore, inhibiting the cytokine storm may be a prophylactic and therapeutic approach toward combating COVID-19 infection (Zimecki et al, 2021).In the study of pulmonary acute respiratory distress syndrome (ARDS) in granulomatous inflammation model (Mrityunjaya et al, 2020), it was found that LF can reduce or eliminate cytokine excess and pulmonary pathological features caused by Mycobacterium tuberculosis (Welsh et al, 2011;Hwang et al, 2017). In addition, LF was also able to diminish hyperacute immunopathology developed after the administration of isolated surface mycolic acid components (Nguyen et al, 2021(Nguyen et al, , 2022. LF significantly induced the expression of the antiviral immune response genes and partially inhibited SARS-CoV-2 infection and replication in Caco-2 intestinal epithelial cells to protect against SARS-CoV-2 infection in vitro (Salaris et al, 2021).…”

Recombinant Human Lactoferrin Reduces Inflammation and Increases Fluoroquinolone Penetration to Primary Granulomas During Mycobacterial Infection of C57Bl/6 Mice

“…Novel approaches to Mtb treatment include host-directed therapies ( Ndlovu and Marakalala 2016 ) which are focused in two major fronts; the first augments immune response using immune-based treatments ( Vilaplana et al 2013 ), while the second alters the resultant immunopathology ( Nguyen et al 2021 ). Examples of immune-based treatment methods include agents that target the macro-autophagic compartment, such as vitamin D and retinoic acid, which increase phagocytosis to enhance the lysosomal degradative processes inside macrophages ( Estrella et al 2011 ).…”

“…Relative to the study described in this report, bovine lactoferrin significantlly reduced inflammatory pathology in Mtb -infected mice ( Welsh et al 2011 ). Both human and bovine lactoferrins were also shown effective to limit inflammation in a non-infectious TDM-induced granuloma mouse model ( Nguyen et al 2021 ; Welsh et al 2010 ).…”

“…Lactoferrin treatment reduced the M1 phenotypic response to TDM, and limits pathological damage in murine lungs ( Nguyen et al 2020 , 2021 ). The lactoferrin treatment also significantly increased penetration of a second-line anti-mycobacterial agent fluoroquinolone into TDM-induced granulomas ( Nguyen et al 2021 ).…”

“…Lactoferrin treatment reduced the M1 phenotypic response to TDM, and limits pathological damage in murine lungs ( Nguyen et al 2020 , 2021 ). The lactoferrin treatment also significantly increased penetration of a second-line anti-mycobacterial agent fluoroquinolone into TDM-induced granulomas ( Nguyen et al 2021 ). Such anti-inflammatory response in the lactoferrin-treated mice, along with other data showing lactoferrin reduces pro-inflammatory phenotypes in macrophages ( Hwang et al 2016 ; Wisgrill et al 2018 ), suggests that lactoferrin had a modulating pro-inflammatory response on granulomas.…”