Pleiotropic Effect of IL-6 Produced by B-Lymphocytes During Early Phases of Adaptive Immune Responses Against TB Infection

Abstract

The role of B cells migrating to the lung and forming follicles during tuberculosis (TB) inflammation is still the subject of debate. In addition to their antibody production and antigen-presenting functions, B cells secrete different cytokines and chemokines, thus participating in complex networks of innate and adaptive immunity. Importantly, lung B-cells produce high amounts of the pleiotropic gp130 cytokine IL-6. Its role during TB infection remains controversial, partly due to the fact that IL-6 is produced by different cell types. To investigate the impact of IL-6 produced by B cells on TB susceptibility and immune responses, we established a mouse strain with specific IL-6 deficiency in B cells (CD19cre-IL-6fl/fl, B-IL-6KO) on the B6 genetic background. Selective abrogation of IL-6 in B cells resulted in shortening the lifespan of TB-infected B-IL-6KO mice compare to the wild-type controls. We provide evidence that at the initial TB stages B cells serve as a critical source of IL-6. In the lung, the effect of IL-6 deficiency in B cells is associated rather with B and T cell functioning, than with macrophage polarization. TB-infected B-IL-6KO mice displayed diminished sizes of B cells themselves, CD4+IFN-γ+, Th17+, and CD4+CXCR5+ follicular T cell populations. The pleiotropic effect of B-cell-derived IL-6 on T-cells demonstrated in our study bridges two major lymphocyte populations and sheds some light on B- and T-cells interactions during the stage of anti-TB response when the host switches on a plethora of acquired immune reactions.

Repurposed Anti-IL-6 Therapeutics, Another Way to Quell the Cytokine Storm in Tuberculosis

“…IL-6 in turn promotes TB production and migration via STAT3 signaling [15]. A complementary source of IL-6 in TB is CD4 + T lymphocytes [16,17]. Increased levels of circulating IL-6 in patients infected by M. tuberculosis predicts TB risk.…”

Potential Roles of Anti-Inflammatory Plant-Derived Bioactive Compounds Targeting Inflammation in Microvascular Complications of Diabetes

“…Numerous studies have already demonstrated an increased level of IL-6 in DNP. It has been reported that IL-6 exerts direct action in infiltrating and glomerular cells, which altered the dynamics of the extracellular matrix affecting GBM thickening [ 130 , 133 ]. IL-6 also affects vascular permeability, extracellular matrix overexpression, and increased proliferation [ 130 ].…”

Metabolic biological markers for diagnosing and monitoring the course of tuberculosis

“…Это приводит к повышению проницае-мости кровеносных сосудов, отеку и усилению миграции лейкоцитов [28]. При деструктивных процессах в легких и образовании каверн обнаруживается высокий уровень MMP-9 в плазме крови пациентов, что может служить коррелятом распада гранулемы [44,47], и вполне объяснимо, что количество нейтрофилов -основных источников веществ, разрушающих целостность тканей в легких -коррелирует с активностью MMP-9 [19,60,68]. Как и в случае с MMР-1, основными ингибиторами синтеза MMP-9 являются витамин D3 и TIMP1 [20].…”

“…Выведенная линия мышей со специфическим дефицитом IL-6 в В-клетках (CD19cre-IL-6fl/fl, B-IL-6KO) продемонстрировала сокращение продолжительности жизни мышей B-IL-6KO, инфицированных туберкулезом, по сравнению с контрольной группой дикого типа. Предполагается, что на начальных стадиях туберкулеза В-клетки служат критическим источником IL-6, отсутствие которого вызывает уменьшение В-клеток и популяций фолликулярных Т-клеток, следовательно эффект IL-6 связан с межклеточным взаимодействием В-клеток и Т-клеток на стадии противотуберкулезного иммунного ответа [47].…”