Increased Escherichia coli-Induced Interleukin-23 Production by CD16⁺Monocytes Correlates with Systemic Immune Activation in Untreated HIV-1-Infected Individuals

Abstract

The level of microbial translocation from the intestine is increased in HIV-1 infection. Proinflammatory cytokine production by peripheral antigen-presenting cells in response to translocated microbes or microbial products may contribute to systemic immune activation, a hallmark of HIV-1 infection. We investigated the cytokine responses of peripheral blood myeloid dendritic cells (mDCs) and monocytes to in vitro stimulation with commensal enteric Escherichia coli in peripheral blood mononuclear cells (PBMC) from untreated HIV-1-infected subjects and from uninfected controls. Levels of interleukin 23 (IL-23) produced by PBMC from HIV-1-infected subjects in response to E. coli stimulation were significantly higher than those produced by PBMC from uninfected subjects. IL-23 was produced primarily by CD16 ؉ monocytes. This subset of monocytes was increased in frequency and expressed higher levels of Toll-like receptor 4 (TLR4) in HIV-1-infected individuals than in controls. Blocking TLR4 on total CD14؉ monocytes reduced IL-23 production in response to E. coli stimulation. Levels of soluble CD27, an indicator of systemic immune activation, were elevated in HIV-1-infected subjects and were associated with the percentage of CD16؉ monocytes and the induction of IL-23 by E. coli, providing a link between these parameters and systemic inflammation. Taken together, these results suggest that IL-23 produced by CD16؉ monocytes in response to microbial stimulation may contribute to systemic immune activation in HIV-1-infected individuals.

The FcγR of Humans and Non-human Primates and Their Interaction with IgG: Implications for Induction of Inflammation, Resistance to Infection and the Use of Therapeutic Monoclonal Antibodies

“…A recent study has shown that CD16+ monocytes from HIV infected patients have increased capacity to produce IL-23 in response to LPS/TLR4 stimulation (Manuzak et al 2013). Fc receptors are likely to play a role in this systemic immune activation since cross talk between FcRs and pattern recognition receptors can shape immune responses by together setting the nature of co-stimulation and the cytokine milieu under which T cell immunity develops.…”

Stimulation of PBMC and Monocyte-Derived Macrophages via Toll-Like Receptor Activates Innate Immune Pathways in HIV-Infected Patients on Virally Suppressive Combination Antiretroviral Therapy

“…Besides, recent literature in both HIV-negative and HIV-positive individuals provided ex vivo evidence for a direct role of translocating microbial products in driving immune activation. In particular, ex vivo stimulation of PBMCs and antigen-presenting cells with bacterial ligands (including LPS), commensal bacteria, and combined bacterial and viral stimulus results in the production of pro- and anti-inflammatory cytokines (36–50). In cART-treated patients, increased CD8+ CD38+ cells have been reported upon LPS exposure in subjects with poor CD4+ T-cell restoration (50) as well as impaired IFN-α production, following stimulation of plasmacytoid dendritic cells with TLR7 and TLR9 agonists (51).…”

MicroRNA miR-126-5p Enhances the Inflammatory Responses of Monocytes to Lipopolysaccharide Stimulation by Suppressing Cylindromatosis in Chronic HIV-1 Infection

“…Preexposure of monocytes to Toll-like receptor 7/8 (TLR7/8) ligands derived from HIV-1 single-stranded RNA (ssRNA) (14,15) and upregulated TLR2 expression on monocytes (16) could enhance the inflammatory responsiveness of these cells. In addition, skewed differentiation of monocytes into proinflammatory CD16 ϩ monocytes and tumor necrosis factor alpha (TNF-␣)-producing M-DC8 ϩ CD14 ϩ CD16 ϩϩ monocytes during chronic HIV-1 infection have been observed in the presence of HIV-1 viremia compared to that observed in HIV-1 seronegative subjects (7,9,17). Effective antiretroviral therapy (ART) successfully suppresses HIV-1 replication but fails to normalize monocyte activation/inflammation (3,(18)(19)(20)(21).…”

“…Preexposure of monocytes to the TLR7/8 pathway triggered by HIV-1 ssRNA-derived ligands has been considered the causative factor for the increased LPS/TLR4 responsiveness (15). Other studies have focused on the skewed differentiation of monocyte subgroups during HIV-1 infection and observed that proinflammatory CD16 ϩ monocytes and TNF-␣-producing M-DC8 ϩ CD14 ϩ CD16 ϩϩ monocytes were more expanded in chronic HIV-1 infection than in healthy subjects (7,9,17,49). Interestingly, the expansion levels of these cells appear to vary among different reports (7,8,49).…”

“…Monocyte activation and inflammation are commonly found in chronic human immunodeficiency virus type 1 (HIV-1) patients (6)(7)(8)(9)(10)(11). The translocation of bacterial derivatives from the compromised gastrointestinal (GI) tract into the blood observed in chronic HIV-infected subjects (1,5,12) and the hyperresponsiveness of monocytes to lipopolysaccharide (LPS) have been considered impor-tant causative factors for persistent immune activation (6,13).…”