Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease

Abstract

Macrophage infiltration of the kidney is a prominent feature associated with the severity of renal injury and progressive renal failure. To determine the influence of macrophages in renal disease models in the absence of endogenous T and B cells, we performed adoptive transfer of macrophages into severe combined immunodeficient (SCID) mice. In this study, macrophages were isolated from the spleens of BALB/c mice and stimulated with lipopolysaccharide to induce classically activated M1 macrophages or with interleukin-4 (IL-4) and IL-13 to induce alternatively activated M2 macrophages. These macrophages were then infused into SCID mice with adriamycin nephropathy; an in vivo model of chronic inflammatory renal disease analogous to human focal segmental glomerulosclerosis. Mice infused with M1 macrophages had a more severe histological and functional injury, whereas M2 macrophage-induced transfused mice had reduced histological and functional injury. Both M1 and M2 macrophages localized preferentially to the area of injury and maintained their phenotypes even after 4 weeks. The protective effect of M2 macrophages was associated with reduced accumulation and possibly downregulated chemokine and inflammatory cytokine expression of the host infiltrating macrophages. Our findings demonstrate that macrophages not only act as effectors of immune injury but can be induced to provide protection against immune injury.

Stem cell options for kidney disease

“…In contrast, inhibition of nuclear factor-κB, a regulator of macrophage functional differentiation, reprogrammes macrophages so that they become profoundly anti-inflammatory in settings where they would normally be classically activated and attenuate glomerular inflammation in vivo [35]. Furthermore, ex vivo manipulation of macrophages using specific cytokines confirmed that classically activated, M1 macrophages worsen chronic inflammatory adriamycin nephropathy, whereas alternatively activated M2 macrophages reduce histological disruption and functional injury [36]. Of note, in the heart Camargo et al [37] have [39] Glycerol-induced ARF (mouse) MSCs Enhanced tubular proliferation [68] IR (rat) Papilla LRCs Proliferation and incorporation [149] IR (mouse) Bone marrow No functional improvement, intrarenal cells are the main source of repopulating cell during repair [22] Folic acid-induced acute tubular injury (mouse) Bone marrow Intrinsic tubular cell proliferation accounts for repair after damage [150] Folic acid-induced acute tubular injury (mouse) Bone marrow 10% incorporation in tubules and G-CSF doubles this rate [151] IR (rat) MSCs Improved renal function and less injury [152] Cisplatin-induced renal failure (mouse) MSCs Accelerated tubular proliferation [153] UUO (mouse) Bone marrow macrophages Reduced renal fibrosis [41] IR (rat) MSCs Improved renal function, increased proliferation and decreased apoptosis [84] IR (rat) rKS56 (S3 segment outgrowth) Replace tubular and improve function [80] Glycerol-induced tubulonecrosis (mouse) Human CD133 + cells Homing and tubular integration [66] UUO (rat) Label-retaining cells (LRC) Proliferates, migrates and transdifferentiates into fibroblast-like cells [27] Cisplatin-induced renal failure (mouse) G-CSF ± M-CSF Improvement in renal function and prevention of renal tubular injury [154] Anti-Thy1.1 GN (rat) MSCs Increased glomerular proliferation and reduction in proteinuria [53] Col4α3 deficiency (mouse) MSCs Prevented loss of peritubular capillaries and reduced fibrosis but no increase in function or survival [24] Col4α3 deficiency (mouse) Bone marrow Partial restoration of expression of the type IV collagen α3 chain, improved histology and function [25] Col4α3 deficiency (mouse) MSCs Improved function and glomerular scarring and interstitial fibrosis reduced [155] UUO (mouse) BM Instertitial BM-derived cells do not contribute significantly to collagen synthesis after damage [74] Adriamycin-nephropathy (mo...…”

Nippostrongylus brasiliensis infection leads to the development of emphysema associated with the induction of alternatively activated macrophages

“…Macrophages exhibiting this AAM phenotype were found in the lung later than 100 days post infection (data not shown). A number of differences in chemokine expression have been described between classical and alternatively activated macrophages [13][14][15]. To further characterize the Mac3 hi CD11b hi hemosiderin-laden macrophages, we assessed CCL5, CXCL11 and CCL17 chemokine expression levels in sorted cells.…”

La fibrose tubulo-interstitielle rénale

“…Les macrophages M1, délétères, produisent des radicaux libres oxygénés et sécrètent des cytokines pro-inflammatoires telles que le TNF- et l'IL-1-. Ces produits étant toxiques pour les cellules résidentes rénales, ils contribuent ainsi à l'extension des lésions et à la progression de la fibrose (Figure 2) [6,7]. À l'inverse, les macrophages de type M2 exercent un rôle protecteur.…”

“…À l'inverse, les macrophages de type M2 exercent un rôle protecteur. En effet, bien qu'ils soient capables de produire du TGF- et de la MEC, phénomènes qui a priori sont associés à un effet pro-fibrosant, leur rôle principal est de réduire l'inflammation grâce à la sécrétion de cytokines antiinflammatoires comme l'IL-10 et l'IL-6 ( Figure 2) [6,7]. Ainsi Wang et al ont mis en évidence que le transfert de macrophages polarisés (Figure 1) [11].…”

“…Dans cette revue, nous analyserons donc quels sont les mécanismes et les facteurs de progression de la FTI et quelles sont les stratégies thérapeutiques envisageables pour l'avenir. < ex vivo vers un phénotype M2 permettait de réduire l'inflammation et le développement de la fibrose rénale chez l'animal alors que le transfert de macrophages de type M1 aggravait les lésions [7]. Bien que les macrophages soient toujours reconnus comme étant les acteurs-clés de l'inflammation associée à la FTI, il est donc désormais nécessaire de mieux caractériser le rôle relatif de ces deux populations.…”