Abstract:
BACKGROUND : Intestinal macrophages are key regulators of inflammatory responses to the gut microbiome and play
a central role in maintaining tissue homeostasis and epithelial integrity. However, little is known about the role of
these cells in HIV infection, a disease fuelled by intestinal inflammation, a loss of epithelial barrier function and
increased microbial translocation (MT).
METHODS : Phenotypic and functional characterization of intestinal macrophages was performed for 23 African AIDS
patients with chronic diarrhea and/or weight loss and 11 HIV-negative Africans with and without inflammatory
bowel disease (IBD). AIDS patients were treated with cotrimoxazole for the prevention of opportunistic infections
(OIs). Macrophage phenotype was assessed by flow cytometry and immuno-histochemistry (IHC); production of
proinflammatory mediators by IHC and Qiagen PCR Arrays; in vitro secretion of cytokines by the Bio-Plex Suspension
Array System. Statistical analyses were performed using Spearman’s correlation and Wilcoxon matched-pair tests.
Results between groups were analyzed using the Kruskal-Wallis with Dunn’s post-test and the Mann–Whitney U tests.
RESULTS : None of the study participants had evidence of enteric co-infections as assessed by stool analysis and
histology. Compared to healthy HIV-negative controls, the colon of AIDS patients was highly inflamed with increased
infiltration of inflammatory cells and increased mRNA expression of proinflammatory cytokine (tumour necrosis factor
(TNF)-α, interleukin (IL)-1β, IFN-γ, and IL-18), chemokines (chemokine (C-C motif) ligand (CCL)2 and chemokine (C-X-C)
motif ligand (CXCL)10) and transcription factors (TNF receptor-associated factor (TRAF)6 and T-box (TXB)21). IHC
revealed significant co-localization of TNF-α and IL-1β with CD68+ cells. As in IBD, HIV was associated with a marked
increase in macrophages expressing innate response receptors including CD14, the co-receptor for lipopolysaccharide
(LPS). The frequency of CD14+ macrophages correlated positively with plasma LPS, a marker of MT. Total unfractionated
mucosal mononuclear cells (MMC) isolated from the colon of AIDS patients, but not MMC depleted of CD14+ cells, secreted increased levels of proinflammatory cytokines ex vivo in response to LPS
CONCLUSIONS : Intestinal macrophages, in the absence of overt OIs, play an important role in driving persistentinflammation in HIV patients with late-stage disease and diarrhea. These results suggest intensified treatmentstrategies that target inflammatory processes in intestinal macrophages may be highly beneficial in restoringthe epithelial barrier and limiting MT in HIV-infected patients.
