Human monocytes store and secrete preformed CCL5, independent of de novo protein synthesis

Persaud, Arvin Tejnarine; Bennett, S.; Thaya, Laxshaginee; Burnie, Jonathan; Guzzo, Christina

doi:10.1002/jlb.3a0820-522rr

Cited by 7 publications

(4 citation statements)

References 75 publications

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“…5B ), we next determined if cytokines can be secreted downstream of the activated transcription factor. The prototypical inflammatory cytokine, TNF-α, is secreted by primary human monocytes and monocytic cell lines upon LPS-induced NF-κB activation ( 59 – 61 ). To that end, we conducted a similar experiment with LPS-loaded virions overlayed onto THP-1 monocytes and then assayed the culture supernatants for secreted TNF-α ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, results from the TLR4 reporter cell line indicated that both NF-κB and IRF3 get activated by CD14 + virions loaded with LPS. Activated NF-κB ( 59 – 61 ) and IRF3 ( 38 , 62 , 63 ), then, were presumably responsible for the secretion of TNF-α and CCL5, respectively, by THP-1 cells. This rationale was partially confounded by the absence of the canonical IRF3 gene target, IFN-β, being secreted by monocytes and macrophages tested herein.…”

Section: Discussionmentioning

confidence: 99%

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Virion-incorporated CD14 enables HIV-1 to bind LPS and initiate TLR4 signaling in immune cells

Persaud,

Khela,

Fernandes

et al. 2024

J Virol

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HIV-1 has a broad range of nuanced interactions with the immune system, and the incorporation of cellular proteins by nascent virions continues to redefine our understanding of the virus-host relationship. Proteins located at the sites of viral egress can be selectively incorporated into the HIV-1 envelope, imparting new functions and phenotypes onto virions, and impacting viral spread and disease. Using virion capture assays and western blot, we show that HIV-1 can incorporate the myeloid antigen CD14 into its viral envelope. Virion-incorporated CD14 remained biologically active and able to bind its natural ligand, bacterial lipopolysaccharide (LPS), as demonstrated by flow virometry and immunoprecipitation assays. Using a Toll-like receptor 4 (TLR4) reporter cell line, we also demonstrated that virions with bound LPS can trigger TLR4 signaling to activate transcription factors that regulate inflammatory gene expression. Complementary assays with THP-1 monocytes demonstrated enhanced secretion of inflammatory cytokines like tumor necrosis factor alpha (TNF-α) and the C-C chemokine ligand 5 (CCL5), when exposed to LPS-loaded virus. These data highlight a new type of interplay between HIV-1 and the myeloid cell compartment, a previously well-established cellular contributor to HIV-1 pathogenesis and inflammation. Persistent gut inflammation is a hallmark of chronic HIV-1 infection, and contributing to this effect is the translocation of microbes across the gut epithelium. Our data herein provide proof of principle that virion-incorporated CD14 could be a novel mechanism through which HIV-1 can drive chronic inflammation, facilitated by HIV-1 particles binding bacterial LPS and initiating inflammatory signaling in TLR4-expressing cells. IMPORTANCE HIV-1 establishes a lifelong infection accompanied by numerous immunological changes. Inflammation of the gut epithelia, exacerbated by the loss of mucosal T cells and cytokine dysregulation, persists during HIV-1 infection. Feeding back into this loop of inflammation is the translocation of intestinal microbes across the gut epithelia, resulting in the systemic dissemination of bacterial antigens, like lipopolysaccharide (LPS). Our group previously demonstrated that the LPS receptor, CD14, can be readily incorporated by HIV-1 particles, supporting previous clinical observations of viruses derived from patient plasma. We now show that CD14 can be incorporated by several primary HIV-1 isolates and that this virion-incorporated CD14 can remain functional, enabling HIV-1 to bind to LPS. This subsequently allowed CD14 + virions to transfer LPS to monocytic cells, eliciting pro-inflammatory signaling and cytokine secretion. We posit here that virion-incorporated CD14 is a potential contributor to the dysregulated immune responses present in the setting of HIV-1 infection.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Virion-incorporated CD14 enables HIV-1 to bind LPS and initiate TLR4 signaling in immune cells

Persaud,

Khela,

Fernandes

et al. 2024

J Virol

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“…Importantly, IL-10 can downregulate MHC class II molecules on monocytes, but specifically HLA-DR on all monocytes and HLA-DM on CD14 + and CD16 + [ 208 ]. Alternative classical monocytes can secrete proinflammatory cytokines such as IL-6, IL-8, and chemokines CCL2, CCL3, and CCL5 [ 209 , 210 ]. Throughout monocyte development, progressive changes in activation and upregulation of CD16 expression can occur with antigen presentation complexes usually accompanied by cytokine secretion of TNF-α, IL-1β, and IL-6 upon TLR stimulation.…”

Section: Inflammatory Cells and Phagocytesmentioning

confidence: 99%

Innate and Adaptive Immunity during SARS-CoV-2 Infection: Biomolecular Cellular Markers and Mechanisms

Brown¹,

Ojha²,

Fricke³

et al. 2023

Vaccines

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The coronavirus 2019 (COVID-19) pandemic was caused by a positive sense single-stranded RNA (ssRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, other human coronaviruses (hCoVs) exist. Historical pandemics include smallpox and influenza, with efficacious therapeutics utilized to reduce overall disease burden through effectively targeting a competent host immune system response. The immune system is composed of primary/secondary lymphoid structures with initially eight types of immune cell types, and many other subtypes, traversing cell membranes utilizing cell signaling cascades that contribute towards clearance of pathogenic proteins. Other proteins discussed include cluster of differentiation (CD) markers, major histocompatibility complexes (MHC), pleiotropic interleukins (IL), and chemokines (CXC). The historical concepts of host immunity are the innate and adaptive immune systems. The adaptive immune system is represented by T cells, B cells, and antibodies. The innate immune system is represented by macrophages, neutrophils, dendritic cells, and the complement system. Other viruses can affect and regulate cell cycle progression for example, in cancers that include human papillomavirus (HPV: cervical carcinoma), Epstein–Barr virus (EBV: lymphoma), Hepatitis B and C (HB/HC: hepatocellular carcinoma) and human T cell Leukemia Virus-1 (T cell leukemia). Bacterial infections also increase the risk of developing cancer (e.g., Helicobacter pylori). Viral and bacterial factors can cause both morbidity and mortality alongside being transmitted within clinical and community settings through affecting a host immune response. Therefore, it is appropriate to contextualize advances in single cell sequencing in conjunction with other laboratory techniques allowing insights into immune cell characterization. These developments offer improved clarity and understanding that overlap with autoimmune conditions that could be affected by innate B cells (B1+ or marginal zone cells) or adaptive T cell responses to SARS-CoV-2 infection and other pathologies. Thus, this review starts with an introduction into host respiratory infection before examining invaluable cellular messenger proteins and then individual immune cell markers.

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“…We used primary classical monocytes (CD14 + CD16 − , henceforth: “monocytes”) [ 16 ], which account for approximately 92% of all human monocytes [ 17 ]. Monocytes secrete a variety of proteins, including pro-inflammatory cytokines such as IL-1β [ 18 ], anti-inflammatory cytokines such as TGFβ [ 19 ] and chemoattractants for various cell types, such as CXCL8 for neutrophils [ 20 ], or CCL5 that attracts both T-lymphocytes and monocytes [ 21 ] as well as the non-canonical Wnt-5a ligand [ 22 ]. Consequently, monocytes play important roles in immune defense, inflammation, tissue remodeling, and self-recruitment/movement to sites of inflammation, which are all critical for the host defense [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Wnt signaling regulates chemokine production and cell migration of circulating human monocytes

Zelikson,

Ben,

Caspi

et al. 2024

Cell Commun Signal

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The β-catenin dependent canonical Wnt signaling pathway plays a crucial role in maintaining normal homeostasis. However, when dysregulated, Wnt signaling is closely associated with various pathological conditions, including inflammation and different types of cancer.Here, we show a new connection between the leukocyte inflammatory response and the Wnt signaling pathway. Specifically, we demonstrate that circulating human primary monocytes express distinct Wnt signaling components and are susceptible to stimulation by the classical Wnt ligand—Wnt-3a. Although this stimulation increased the levels of β-catenin protein, the expression of the classical Wnt-target genes was not affected. Intriguingly, treating circulating human monocytes with Wnt-3a induces the secretion of cytokines and chemokines, enhancing monocyte migration. Mechanistically, the enhanced monocyte migration in response to Wnt stimuli is mediated through CCL2, a strong monocyte-chemoattractant.To further explore the physiological relevance of these findings, we conducted ex-vivo experiments using blood samples of patients with rheumatic joint diseases (RJD) – conditions where monocytes are known to be dysfunctional. Wnt-3a generated a unique cytokine expression profile, which was significantly distinct from that observed in monocytes obtained from healthy donors.Thus, our results provide the first evidence that Wnt-3a may serve as a potent stimulator of monocyte-driven immune processes. These findings contribute to our understanding of inflammatory diseases and, more importantly, shed light on the role of a core signaling pathway in the circulation.

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Human monocytes store and secrete preformed CCL5, independent of de novo protein synthesis

Cited by 7 publications

References 75 publications

Virion-incorporated CD14 enables HIV-1 to bind LPS and initiate TLR4 signaling in immune cells

Virion-incorporated CD14 enables HIV-1 to bind LPS and initiate TLR4 signaling in immune cells

Innate and Adaptive Immunity during SARS-CoV-2 Infection: Biomolecular Cellular Markers and Mechanisms

Wnt signaling regulates chemokine production and cell migration of circulating human monocytes

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