Characterisation of the myeloid CSF1R+ dendritic cell subsets and monocytes in health and disease
Creators: name: Orsenigo, Federica
Publisher: name: University of Surrey
Year: 2023

description: Dendritic cells (DCs) and monocytes are innate immune cells involved in recognising pathogens or damage-associated molecules, triggering adaptive immune responses, and maintaining homeostatic conditions. DCs and monocytes are collectively referred to as Mononuclear Phagocyte System (MPS) cells, and their origin and development in humans still need elucidating. Lineage-determining cytokine receptors (LDCRs) are growth factors with a pivotal role in haematopoietic cell differentiation and survival. These receptors are retained on mature cell surface, suggesting an active role after differentiation. Here, the link between DCs and monocytes at a developmental level was assessed at steady state using CSF1R, aLDCR previously known as expressed only on macrophages, but now proved to be on all cells of the MPS. The MPS was further studied across multiple diseases, to assess its development or effector state. DCs and monocytes were assessed in two distinct anti-malarial vaccine challenges. Both vaccines targeted the same blood-stage Plasmodium falciparum antigen apical membrane protein 1 (AMA1),involved in erythrocyte invasion by malaria. One vaccine formulation was based on a prime-boost viral delivery of the antigen, while the other vaccine consisted of the recombinant protein administered with a liposome-based adjuvant system. The MPS was greatly affected and reshaped, with cell fluctuations in percentages depending on the vaccine formulation. The viral-vectored vaccine also seemed to activate cells more effectively compared to the protein vaccine. LDCR and surface marker expression in CSF1R+ cells was also affected by the different vaccine vector components.
description: DCs also play a role in infectious diseases. In the global pandemic of COVID-19,understanding how the MPS is modulated by the SARS-CoV-2 virus was crucial, especially for elderly people and individuals with underlying conditions. Two South African COVID patients’ cohorts were investigated, where HIV and Tb coinfections, steroid treatment,and other comorbidities where present. There was a direct variant-dependent impact of COVID-19 on the MPS. In COVID-19 patients,there was a decrease in circulating CSF1R+ MPS cells, enhanced by the presence of certain comorbidities such as hypertension and diabetes. Aside from underlying conditions, one of the causes of poor prognosis is a phenomenon called cytokine storm and it is linked to the MPS cells. The elevated levels of circulating cytokines released by the MPS cells interact with the complement and coagulation systems to induce coagulation, respiratory and multi-organ failure. Therefore, DCs and monocyte ability to activate their NLRP3 inflammasome and release pro-inflammatory cytokines was investigated. The CD14+monocytic compartment and DCs were able to respond to NLRP3 activating stimuli by releasing interleukin 1 β and undergoing cell death, signs of activation of an inflammasome pathway. Finally, the role of DCs and monocytes was investigated in the context of another pathological setting, with the comparison of two different types of tumours that usually display different immune infiltrated. The first tumour, lung adenocarcinoma (LUAD), is conventionally referred toas “hot” or immune infiltrated tumour, while the second, colorectal cancer (CRC), as “cold” or immune excluded. The comparison between these two tumours was pursuit using public single-cell RNA sequencing datasets. Different expression of CSF1R and CSF2R were noted across tumoral tissues, and a specific type of DCs recently discovered and poorly characterised at functional level displayed opposite behaviour, accumulating in LUAD but not in CRC. For this DC subset, a putative tolerogenic role was proposed that would need tobe validated with functional studies.
description: This work underlined the importance of investigating the involvement of CSF1R+ MPS cells in health and diseases and provided a pan-MPS marker for human studies.