Peritoneal macrophage heterogeneity is associated with different peritoneal dialysis outcomes

Abstract

Peritonitis remains the major obstacle for the maintenance of long-term peritoneal dialysis and dysregulated host peritoneal immune responses may compromise local anti-infectious defense, leading to treatment failure. Whilst, tissue mononuclear phagocytes, comprising macrophages and dendritic cells, are central to a host response to pathogens and the development of adaptive immune responses, they are poorly characterized in the human peritoneum. Combining flow cytometry with global transcriptome analysis, the phenotypic features and lineage identity of the major CD14+ macrophage and CD1c+ dendritic cell subsets in dialysis effluent were defined. Their functional specialization was reflected in cytokine generation, phagocytosis, and antigen processing/presentation. By analyzing acute bacterial peritonitis, stable (infection-free) and new-starter patients receiving peritoneal dialysis, we identified a skewed distribution of macrophage to dendritic cell subsets (increasing ratio) that associated with adverse peritonitis outcomes, history of multiple peritonitis episodes, and early catheter failure, respectively. Intriguingly, we also noted significant alterations of macrophage heterogeneity, indicative of different maturation and activation states that were associated with different peritoneal dialysis outcomes. Thus, our studies delineate peritoneal dendritic cells from macrophages within dialysate, and define cellular characteristics associated with peritoneal dialysis treatment failure. These are the first steps to unravelling the detrimental adaptive immune responses occurring as a consequence of peritonitis.

Human dendritic cell subsets: an update

“…In humans, inflammatory myeloid cells have been reported in several settings including eczema, 186 psoriasis, 187,188 skin sensitization, 189 allergic rhinitis, 190 coeliac disease, 191 inflammatory bowel disease, 192,193 synovitis and peritonitis. 24,194 Kinetics, surface markers, gene expression and even direct labelling suggest that monocytederived cells dominate these populations. Considerable heterogeneity is observed with no clear consensus on the use of the terms monocyte, macrophage or DC to describe inflammatory monocyte-derived cells ( Table 2).…”

“…Inflammatory monocytes retain expression of CD13, CD33, CD11b, CD11c and CD172a and may show recent evidence of recruitment from monocytes by their expression of S100A8/9 and CCR2. 190,194 In humans, monocytes express CD11c and MHC class II so these markers are not helpful in separating monocytes from DC. Evidence of DC differentiation is supported by the expression of CD1c, CD1a, FceR1, IRF4 and ZBTB46.…”

“…CD14 was variable but CD16 and CD163 were negative. 24,194 Although gene expression showed subsetrestricted patterns, there were many shared transcripts between populations designated as mo-DC and those described as monocyte-derived macrophages.…”

“…During inflammation, monocyte-derived cells expand resident populations many-fold. [189][190][191][192][193][194] Prevailing models suggest that monocyte-derived cells function mainly at a site of inflammation rather than migrating to lymph nodes. 195 However, mo-DC studied ex vivo secrete IL-1, TNF-a, IL-12 and IL-23, stimulate CD4 and CD8 T cells and express CCR7.…”

“…195 However, mo-DC studied ex vivo secrete IL-1, TNF-a, IL-12 and IL-23, stimulate CD4 and CD8 T cells and express CCR7. 24,188,194 Although it is possible to derive potent mo-DC in vitro with GM-CSF and IL-4 followed by activating stimuli such as lipopolysaccharide or prostaglandin E 2 , the use of such preparations in immunotherapy is declining in favour of 'naturally-occurring' DC such as pDC or cDC2 (reviewed in ref. 196).…”