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Editorial: Macrophages and Dendritic Cells in Motion: Tracking Inflammation and Fibrosis

Lupus nephritis affects approximately one-third of patients with systemic lupus erythematosus (SLE) and is a major cause of morbidity and mortality. Understanding the unique cellular microenvironment within the kidney is likely to lead to improved diagnostic and therapeutic approaches in patients with lupus nephritis. What is the significance of increased numbers of renal macrophages in lupus nephritis? In studies of renal biopsy specimens obtained from patients with lupus, increased numbers of macrophages correlated with the severity of renal damage (1 3). Hill et al determined that increased numbers of glomerular macrophages were the most sensitive glomerular morphologic variable in initial biopsy specimens obtained from patients with newly diagnosed renal disease, and that in biopsy specimens obtained after 6 months of therapy, the presence or absence of glomerular monocytes was a significant prognostic indicator of poor clinical and outcome parameters. Moreover, in the second biopsy specimen, the presence or absence of tubular luminal macrophages had the strongest predictive power among morphologic variables for outcome measures (1). Studies in animal models have suggested that macrophages contribute to renal damage, because inhibition of monocyte influx or macrophage activation prevented or slowed the progression of nephritis (4,6 10). What’s in the name macrophage? In light of the observations regarding the relative importance of macrophages in renal disease, Sahu and colleagues conducted extensive phenotyping, morphologic, and functional assessments in order to construct a detailed picture of renal mononuclear phagocytes from 2 different strains of lupus-prone mice (4). In their study, which appears in this issue of Arthritis & Rheumatology, Sahu et al describe 3 renal dendritic cell (DC) populations and 2 renal macrophage populations (4). Their work represents a comprehensive first look at the potential phenotypic and functional heterogeneity that has been denoted by the term “macrophage” in many studies of biopsy specimens obtained from patients with lupus (1 3). As shown in Table 1, Sahu and colleagues used several wellestablished markers to delineate murine renal myeloid cells (4 6). The human counterparts of these markers have been described in recent renal biopsy surveys without functional studies (10). Initially, a major distinction in the determination of myeloid lineage fate was the notion that macrophages were highly phagocytic, while DCs were, by definition, potent antigen-presenting cells. Recent studies have demonstrated that macrophages and DCs often share both phagocytic and antigen-presenting functions. Previous human renal biopsy studies presented rather vague location-based classification schemes to describe subsets of macrophages (1 3). Macrophages have been classified based on the expression of macrophage-specific markers, primarily with a PGM1 monoclonal antibody that identifies the lysosome-associated CD68 glycoprotein in combination with location as in “glomerular” or “extraglomerular CD68 macrophages” (2), or location by compartment, such as “glomerular capillary luminal macrophages” or “PGM1 marker positive cells within tubular epithelium” (1 3). Both murine and human renal studies have shown that distinct myeloid cell subsets accumulated in specific areas of the kidney during chronic disease (1 10). Recent efforts have demonstrated that a substantial number of CD68 cells also expressed DC subset–specific markers in human kidneys, and that these cells accumulated both in the glomerular tuft and in the tublointerstitium in lupus nephritis. Some but not all DC subsets variably expressed CD68 in human renal biopsy specimens (10). Thus, in previous human renal biopsy studies, different subtypes of myeloid cells resided under the umbrella of “macrophage.” Further phenotypic and functional studies carried out in concert Laurie S. Davis, PhD: University of Texas Southwestern Medical Center, Dallas. Address correspondence to Laurie S. Davis, PhD, University of Texas Southwestern Medical Center, Department of Internal Medicine, Rheumatic Diseases Division, 5323 Harry Hines Boulevard, Building Y, Room 206 (Y8.206), Dallas, TX 75390-8884. E-mail: Laurie.Davis@utsouthwestern.edu. Submitted for publication December 20, 2013; accepted in revised form February 11, 2014.