M2 Macrophages in Glomerular Inflammation in Transplant Biopsies: A Possible Role in Microvascular Remodeling.

Abstract

Introduction: Macrophages constitute an essential component of innate immunity, but perform also many homeostatic functions, including tissue remodeling. The latter is associated with the M2 polarized macrophage phenotype, in contrast to the proinflammatory M1 polarized phenotype. The M2 polarized phenotype has been associated in other systems (tumor invasive growth) with disruption of the basal lamina/basement membrane. Since macrophages have been generally associated with antibody mediated rejection (AMR) microvascular lesions and portend a worse prognosis, a more detailed study into their subtypes was undertaken in order to better understand the pathophysiology of this process. Materials and Methods: We performed CD206 immunstains for identification of M2 polarized macrophages in renal transplant biopsies with documented increase in glomerular macrophages (>12 CD68 staining cells in the most inflamed glomerulus), provided that electron microscopic studies (EM) were available, in addition to the full histological work up routinely used for evaluation of transplant biopsies. 52 biopsies qualified for this study. Results: M2 polarized macrophages constitute a major component of the glomerular macrophages (73% on average). Their numbers correlate with the Banff glomerulitis (g, p=.049), chronic transplant glomerulopathy (cg, p=.012) and mesangial matrix deposition (mm, p=.05) scores. More importantly, M2 polarized macrophages correlate with the ultrastructural number of peritubular capillary basal lamina layers (a diagnostic feature of AMR specifically related to microvascular remodeling) (r=.41, p=.003) and time post-transplantation (r=.28,p=0.47). Conclusions: Macrophages are a key morphological component of AMR and its characteristic microvascular pathology. Macrophages, however, display a wide functional and phenotypic spectrum. This study indicates that a major pathogenetic role in transplant glomerular/microvascular pathology is most probably played not by the powerful pro-inflammatory function of these cells (M1), but rather by their smoldering, tissue remodeling -particularly microvasculature basal lamina dissolution/remodeling properties.