Transcriptional Regulation of CXCL5 in HIV-1-Infected Macrophages and Its Functional Consequences on CNS Pathology

Abstract

Human immunodeficiency virus-1 (HIV-1)-infected monocytes/macrophages and microglia release increased levels of proinflammatory cytokines and chemokines, including ELR + (containing glutamic acid-leucine-arginine motif) chemokines. To investigate the role of HIV-1 infection on chemokine regulation, monocyte-derived macrophages (MDMs) from normal donors were infected with HIV-1 and the expression of chemokines and their downstream biological functions were evaluated. Among the tested chemokines, CXCL5 was upregulated significantly both at the mRNA and protein level in the HIV-1-infected MDMs compared with mock-infected cultures. Upregulation of CXCL5 in the HIV-1-infected MDMs is, in part, regulated by increased interleukin-1b (IL-1b) production and phosphorylation of ERK1/2. Functional analyses indicate that HIV-1-induced overexpression of CXCL5 has enhanced the ability to attract neutrophils, as observed by chemotaxis assay. However, exposure of NT2, SH-SY5Y cells, and primary neurons to HIV-1-infected MDM supernatants resulted in cell death that was not rescued by anti-CXCL5 antibody suggesting that CXCL5 does not have direct effect on neuronal death. Together, these results suggest that the increased level of CXCL5 in tissue compartments, including the central nervous system of HIV-1-infected individuals might alter the inflammatory response through the infiltration of neutrophils into tissue compartment, thus causing secondary effects on resident cells.

Heart-resident CCR2+ macrophages promote neutrophil extravasation through TLR9/MyD88/CXCL5 signaling

“…It remains to be defined whether differences in target organs, the nature and severity of the inflammatory insult, the cells producing CXCL5, or local processing of CXCL5 contribute to dissimilarities in neutrophil recruitment in these models. To this end, previous studies have suggested that CXCL5 can be produced by hematopoietic as well as stromal cells, and we have shown that expression of this neutrophil chemokine is regulated by signaling through MyD88 in cardiac macrophages (36, 37). …”

Increased plasma levels of epithelial neutrophil-activating peptide 78/CXCL5 during the remission of Neuromyelitis optica

“…In addition, inhibitors of neutrophil elastase, which are involved in neutrophil migration and neutrophil-mediated tissue damage, have been tested in experimental trials such as Sivelestat [ 7 , 33 – 35 ]. Other studies also indicated that the increased ENA 78 amplified the pro-inflammatory cytokine response, which had a direct chemo-attracting effect on neutrophils [ 36 – 39 ]. Therefore, we studied ENA 78 and found that it was dramatically increased in the NMO patients (vs. HC, P < 0.001; vs. MS, P < 0.05).…”

Chronic Effects of Ethanol and/or Darunavir/Ritonavir on U937 Monocytic Cells: Regulation of Cytochrome P450 and Antioxidant Enzymes, Oxidative Stress, and Cytotoxicity

“…Following their infection with HIV, M/M are known to mediate the transmigration of HIV infection across the blood–brain barrier (Williams et al., ). Several studies have identified specific changes facilitating the spread of HIV infection to brain by M/M (Buckner et al., ; Guha et al., ). A direct evidence supporting the involvement of these cells in HIV propagation and maintenance has been demonstrated previously (Collins et al., ; Harman et al., ; Kramski et al., ).…”