Type-2 diabetes alters the basal phenotype of human macrophages and diminishes their capacity to respond, internalise, and control Mycobacterium tuberculosis

Abstract

BACKGROUND Type 2 diabetes (T2D) is a risk factor for the development of tuberculosis (TB), although the associated mechanisms are not known.OBJECTIVES To study the association between T2D and the basal phenotype of macrophages, and their immune response to Mycobacterium tuberculosis (Mtb) infection.METHODS We evaluated the influence of T2D on the response of monocyte-derived macrophages (MDM) to Mtb in patients with T2D (n = 10) compared to healthy subjects (n = 9), before and after infection with Mtb clinical isolates bearing different degrees of virulence. The levels of cell surface markers for activation secreted cytokines and chemokines, bacterial association, and intracellular bacterial growth were evaluated.FINDINGS The expression levels of HLA-DR, CD80, and CD86 were low while those of of PD-L1 were high in uninfected MDMs derived from patients with diabetes; as a result of Mtb infection, changes were only observed in the expression levels of PD-L1. The levels of cytokines (e.g., IL-6, IL-1β, IL-10, and IL-12) and chemokines (e.g., MCP-1, MIG, and RANTES) are perturbed in MDMs derived from patients with diabetes, both before infection and in response to Mtb infection. In response to the more virulent Mtb strains, the levels of association and bacterial clearance were diminished in MDMs derived from patients with diabetes.CONCLUSIONS T2D affects the basal activation state of the macrophages and its capacity to respond and control Mtb infection.

BCG and BCGΔBCG1419c protect type 2 diabetic mice against tuberculosis via different participation of T and B lymphocytes, dendritic cells and pro-inflammatory cytokines

“…T2D generates a series of changes that compromises the host response against M. tuberculosis, as recently reviewed by some authors 6,7 , including altered capacity to present antigens by macrophages 8 , activation of monocytes 9 , and chemoattraction of immune cells to lung during infection 10 . Furthermore, T2D favors more severe manifestations of TB as compared with those occurring in patients without T2D 11 , including extended lung damage especially at chronic stages of the comorbidity 12,13 .…”

Slow radiological improvement and persistent low-grade inflammation after chemotherapy in tuberculosis patients with type 2 diabetes

“…Enhanced IL-10 levels in the periphery but reduced IL-10 in sputum cells from TB-DM patients at follow up, may also indicate that IL-10 producing cells fail to migrate properly from the peripheral circulation to the Mtb-infected lung. In support of this, the low IL-10 production capacity of immune cells and reduced anti-in ammatory function of IL-10 have been reported in TB-DM disease compared to TB alone [60,61]. While IL-10 could contribute to unwanted immunosuppression of Mtb-speci c immune responses [62,63], it is also necessary to control local pathological in ammation and sustain an environment that limits Mtb replication [64].…”

Slow radiological improvement and persistent low-grade inflammation after chemotherapy in tuberculosis patients with type 2 diabetes

“…Enhanced IL-10 levels in the periphery but reduced IL-10 in sputum cells from TB-DM patients at follow up, may also indicate that IL-10 producing cells fail to properly migrate from the peripheral circulation to the Mtb-infected lung. Low IL-10 production capacity of immune cells and reduced anti-inflammatory function of IL-10 have been reported in TB-DM disease compared to TB alone [53,54]. While IL-10 could contribute to unwanted immunosuppression of Mtb-specific immune responses [55,56], it is also necessary to control local pathological inflammation and sustain an environment that limits Mtb replication [57].…”