Abstract
BackgroundIntestinal 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).MethodsPhenotypic 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.ResultsNone 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.ConclusionsIntestinal macrophages, in the absence of overt OIs, play an important role in driving persistent inflammation in HIV patients with late-stage disease and diarrhea. These results suggest intensified treatment strategies that target inflammatory processes in intestinal macrophages may be highly beneficial in restoring the epithelial barrier and limiting MT in HIV-infected patients.
Highlights
Intestinal macrophages are key regulators of inflammatory responses to the gut microbiome and play a central role in maintaining tissue homeostasis and epithelial integrity
Intestinal macrophages, in the absence of overt Opportunistic infections (OIs), play an important role in driving persistent inflammation in human immunodeficiency virus type (HIV) patients with late-stage disease and diarrhea. These results suggest intensified treatment strategies that target inflammatory processes in intestinal macrophages may be highly beneficial in restoring the epithelial barrier and limiting microbial translocation (MT) in HIV-infected patients
These results suggest that CD14+ macrophages in the colon of African Acquired Immune Deficiency Syndrome (AIDS) patients presenting with diarrhea and/or weight loss may have increased responsiveness to microbial products, a finding that would be expected to perpetuate the local inflammatory response
Summary
Intestinal macrophages are key regulators of inflammatory responses to the gut microbiome and play a central role in maintaining tissue homeostasis and epithelial integrity. 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). Damage includes an early massive depletion of the T helper (Th) subset of CCR5+CD4+ memory T cells [1,2,3,4,5,6,7], changes in the frequency of CD4+CD25+FoxP3+ T regulatory (Treg) cells [8,9,10], an influx of activated cytotoxic CD8+ T lymphocytes [11], irreversible activation-induced fibrosis [12, 13] and a loss of epithelial integrity leading to increased microbial translocation (MT) [14]. Diarrhea accompanied by wasting (“slims disease”) is responsible for a significant amount of HIV-related morbidity in sub-Saharan Africa [22], even in the era of ART [23, 24]. Prophylactic treatment with cotrimoxazole has been shown to improve survival and reduce morbidity in HIV patients prior to the initiation of ART [25,26,27,28]
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