Monocyte connective tissue =. Importantly, M-CSF deficiency affects macrophages with both prenatal and adult hematopoietic origins. The https:// ensures that you are connecting to the Transcriptional profiling identifies Id2 function in dendritic cell development. Recruitment and proliferation appear to be intertwined. Differential rates of replacement of human dermal dendritic cells and macrophages during hematopoietic stem cell transplantation. London A, Cohen M, Schwartz M. Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair. Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM. Morphological heterogeneity of F4/80+ microglia in the adult mouse brain. Gordon S, Plddemann A, Martinez Estrada F. Immunol Rev. First, unlike Runx1CreER, Csf1rCreER is a transgene and might not report native gene expression in all conditions. However, at later time points substantial numbers of resident macrophages can be recovered, which suggests that some resident macrophages remain at the inflammatory site, presumably not recovered earlier because of increased adherence29. In a subsequent fate mapping study, adult microglia, splenic red pulp macrophages, alveolar macrophages and F4/80hi peritoneal cavity macrophages were likewise confirmed to have a prenatal origin and do not rely on blood monocytes for their renewal, at least under steady-state conditions22. Careers, Correspondence should be addressed to: P.R.T. The classical complement cascade mediates CNS synapse elimination. Liu H, et al. The situation in the gastrointestinal tract provides another unique perspective, as blood monocytes are continually recruited to this tissue where they give rise to a resident population that produces IL-10 and which are resistant to Toll-like receptor signals. Sawyer RT, Strausbauch PH, Volkman A. Resident macrophage proliferation in mice depleted of blood monocytes by strontium-89. Enhanced apoptosis in the resting state (Gautier et al., 2014) and a failure to proliferate in states of inflammation (Rosas et al., 2014) explain the loss of macrophages. One study of vesicular stomatitis virus showed that the type-1 IFN response is suppressed in metallophilic macrophages allowing them to become a reservoir of replicating virus that drives an effective adaptive immune response112. The Please enable it to take advantage of the complete set of features! 2019 Mar;97(3):258-267. doi: 10.1111/imcb.12236. Alveolar macrophages reside on the epithelial surface of the lung, and in contrast to other resident macrophage populations, they are in direct contact with the environment, which includes commensal bacteria, inhaled particulates, and host-epithelial-derived factors, such as surfactants. Some of the most critical roles of tissue-resident macrophages may prove to be in energy homeostasis. Schematic representation of regional differences of splenic macrophages in the red and white pulp, as well as the marginal zone. Classically activated macrophages (M1) induced by interferon- (IFN-) or endotoxin promote interleukin-12 (IL12)-mediated T helper 1 (T H 1) immune responses. To what extent is there redundancy between adult-monocyte-derived macrophages and different resident macrophage subsets? Unlike neutrophils, which are short-lived, macrophages can live for months to years. The identification of the monocyte-macrophage dendritic cell (DC) progenitor (MDP) provided a developmental link between both DCs and monocytes within a common differentiation pathway (Fogg et al., 2006). Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, De Nardo D, Gohel TD, Emde M, Schmidleithner L, et al. Furthermore, understanding the distinct developmental origins of many tissue resident macrophage populations, including their need for renewal during homeostasis and disease, will provide insights into fundamental differences between inflammatory monocyte-derived macrophages and their tissue resident cousins. Marn-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M. Microglia promote the death of developing Purkinje cells. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. What is the extent of tissue macrophage plasticity? Trophic macrophages in development and disease. Storer M, Mas A, Robert-Moreno A, Pecoraro M, Ortells MC, Di Giacomo V, Yosef R, Pilpel N, Krizhanovsky V, Sharpe J, Keyes WM. 8600 Rockville Pike For example, similar to depletion of cardiac macrophages, clodronate-liposome-mediated depletion results in profound and permanent loss of embryonically established resident tissue macrophages, including liver Kupffer cells and splenic red-pulp macrophages. 2020 Jun 16;52(6):957-970. doi: 10.1016/j.immuni.2020.05.014. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Origins and functions of phagocytes in the embryo. Alternative activation is associated with allergy, parasitic infection, repair and fibrosis. Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy. After birth, a massive expansion of microglia cell numbers is driven exclusively through in situ proliferation via M-CSF and interleukin-34 (IL-34) without monocyte input (Wegiel et al., 1998; Wang et al., 2012; Ginhoux et al., 2010; Ajami et al., 2007). Below, we will discuss in detail experimental evidence that undergirds the recently revised view of macrophage origins and identify both the strengths and the limitations of each approach (see a summary of tools used for defining macrophage origin in Table 1). Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6C(hi) monocyte precursors. A working model is that mature macrophages have undergone epigenetic changes that prevent such induction, such that GATA6 has not yet been demonstrated to be induced in monocytes or other macrophages from adult mice. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimers disease. Microglia-induced neuronal cell death is accompanied by minimal inflammation and rapid phagocytosis of apoptotic neurons. Keywords: Around the time of birth, bone marrow haemopoietic stem cells (, Selected plasma membrane receptors that mediate macrophage recognition of microbial and host ligands. Defining key transcriptional control elements should provide opportunities to manipulate one branch of the family preferentially, for example to modulate the activity of inflammatory monocyte-derived macrophages whilst limiting impact on homeostatic tissue resident macrophage functions, and vice versa. Macrophages are required for adult salamander limb regeneration. Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration. Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. 2020 Mar 17;52(3):434-451. doi: 10.1016/j.immuni.2020.02.015. Gautier EL, et al. Are we missing critical insight by not parsing macrophage function on the basis of origin? Before These findings were extended using Myb-deficient mice that lack development of hematopoietic stem cells. Functions of tissue-resident macrophages. government site. The development of both marginal zone and metallophilic macrophages is regulated by the nuclear receptor LXR1 (Nr1h3)109. Kang K, et al. Appearance of macrophages tohistologists have been described as a kind of mythological Proteus, a creature who had the power of changing his appearance at will. Alveolar macrophages normally live independently of blood monocyte input; however, an interesting competition takes place if alveolar macrophages are depleted. 2022 Oct 25;2022:9668610. doi: 10.1155/2022/9668610. Chihara T, et al. Paracetamol reduces influenza-induced immunopathology in a mouse model of infection without compromising virus clearance or the generation of protective immunity. However, the use of irradiation and bone-marrow-transplantation models to localize CCR2 deficiency to the bone marrow compartment, which, as stated above, might allow circulating monocytes access to the brain, suggests that formal proof that monocytes enter the CNS in Alzheimers models is currently lacking. In 1968 van Furth and Cohn showed that major populations of macrophages were derived from blood monocytes5. Identification of Tim4 as a phosphatidylserine receptor. In addition, studies using irradiation chimeras with donor cells that are deficient in either Csf1r of Csf2rb have highlighted the differential requirement for M-CSF versus GM-CSF in the reconstitution by proliferation of splenic red pulp and bone marrow macrophages versus lung macrophages, respectively30. . Studies, largely involving complement-deficiency, led to the development of the waste disposal hypothesis of autoimmunity, in which defective clearance of autoantigens present on apoptotic cells drives the development of disease79. Once an intruder is identified, it will phagocytise and destroy the microbe. Kodama H, Nose M, Niida S, Yamasaki A. This process is hypothesized to help maintain tolerance by the appropriate disposal of self antigen80. Such methods however, likely deplete multiple populations of macrophages, and the specific roles of particular sub-populations need to be determined. Front Oncol. Gautier EL, et al. Adipose tissue inflammation, involving increased infiltration of M1 pro-inflammatory macrophages, adipocyte death and abnormal cytokine and adipokine secretion, is a major actor of obesity-induced chronic systemic inflammation and insulin resistance . Aurora AB, Porrello ER, Tan W, Mahmoud AI, Hill JA, Bassel-Duby R, Sadek HA, Olson EN. However, wide variation in receptor usage from tissue to tissue is evident (www.immgen.org) reflecting unique phenotypes in distinct microenvironments. Unlike neutrophils, which are short-lived, macrophages can live for months to years. Save my name, email, and website in this browser for the next time I comment. Huang WC, Yang CC, Chen IH, Liu YM, Chang SJ, Chuang YJ. The myeloid 7/4-antigen defines recently generated inflammatory macrophages and is synonymous with Ly-6B. SIGN-R1 contributes to protection against lethal pneumococcal infection in mice. Muoz-Espn D, Caamero M, Maraver A, Gmez-Lpez G, Contreras J, Murillo-Cuesta S, Rodrguez-Baeza A, Varela-Nieto I, Ruberte J, Collado M, Serrano M. Programmed cell senescence during mammalian embryonic development. A macrophage cell capturing bacteria. GATA6 is a transcription factor that selectively regulates peritoneal macrophage transcripts (Gautier et al., 2014; Gautier et al., 2012b; Okabe and Medzhitov, 2014; Rosas et al., 2014). Macrophages are present in all vertebrate tissues, from mid-gestation throughout life, constituting a widely dispersed organ system. Monocyte chemoattractant protein-1 deficiency does not affect steatosis or inflammation in livers of mice fed a methionine-choline-deficient diet. Detailed analysis of fetal-liver-derived macrophages suggests that this subset is outcompeted over time by RAG1-independent macrophages (derived from fetal monocytes and/or the yolk sac). ATPase, Na+/K+ transporting, alpha 1 polypeptide. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Clear validation of this approach can be seen by the identification of Spi-C transcriptional networks in splenic red pulp macrophages after the discovery that Spi-C plays a critical role in red pulp macrophage development103. Nguyen KD, et al. One consequence of long-term maintenance of a prenatal population would be the requirement for self-renewal via proliferation. Careful examination of skin HLA-DR+ myeloid cells from patients receiving sex-mismatched bone marrow transplants demonstrated that DC populations reached nearly 100% chimerism within 40 days posttransplant, indicating a clear dependency on circulating cells (Haniffa et al., 2009). In normal mice, these cells co-exist with F4/80lo macrophages, which have hematopoietic origins. Mus musculus. Conversely, it might be tempting to assume that Flt3-Cre+ tissue macrophages are continually replenished by Flt3-Cre+ circulating blood monocytes. Karlsson MC, et al. Hettinger J, et al. Immunity. Macrophage receptors and immune recognition. This damage is generally the result of an injury, and quite rare. Their unique staining results from apoptotic cell debris and associated chromatin, which is derived from the phagocytic clearance of dead, activated lymphocytes that result from the germinal center reaction100. Randolph GJ. Federal government websites often end in .gov or .mil. Macrophage expansion in tissues during disease is common and critically modulates injury versus healing. Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, Libby P, Weissleder R, Pittet MJ. Tissue-resident macrophages. Synaptic pruning by microglia is necessary for normal brain development. Biers C, Carrelha J, Lutteropp M, Luc S, Green JC, Azzoni E, Woll PS, Mead AJ, Hultquist A, Swiers G, et al. official website and that any information you provide is encrypted Jakubzick C, Gautier EL, Gibbings SL, Sojka DK, Schlitzer A, Johnson TE, Ivanov S, Duan Q, Bala S, Condon T, et al. Barth MW, Hendrzak JA, Melnicoff MJ, Morahan PS. Merad M, et al. The purpose of this behavior has recently been elucidated. Macrophages that encourage inflammation are called M1 macrophages, whereas those that decrease inflammation and encourage tissue repair are called M2 macrophages. The goal of this review is to highlight emerging questions in the field, such as to what extent macrophage ontogeny versus the tissue niche dictates a macrophages function. Multiple studies have suggested that recruitment of CCR2+ (Ly6chi) monocytes improves clearance of plaque depositions, improves cognitive function, and decreases mortality in animal models of Alzheimers disease, suggesting a clear protective role for infiltrating monocytes (Naert and Rivest, 2011; El Khoury et al., 2007). Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. Mildner A, et al. These range from dedicated homeostatic functions, such as clearance of cellular debris and iron processing, to central roles in tissue immune-surveillance, response to infection and the resolution of inflammation. In the peritoneal cavity and other tissues, these cells have been suggested to exit via the lymphatics or recirculate58, 66, 67. Cell Name Anatomical Location; Monocytes: Bone marrow / blood: Kupffer cells: Liver: Sinus histiocytes: Lymph nodes: . The prolonged lifespan of alveolar macrophages. These results indicate many resident macrophages remain throughout inflammation. There is significant evidence that early in disease progression, recruited monocytes enter into plaque, take up cholesterol, and become dysfunctional foam cells. During the period of acute neutrophil influx, fewer numbers of resident F4/80hiTim4+ macrophages can be recovered from the inflamed tissue. These tissue monocytes can transport antigens to lymph nodes with minimal differentiation changes from their state in blood, although a proportion can convert to Ly6Clo monocytes. Circulating monocytes enter the spleen and upregulate SpiC, leading to macrophage differentiation, reestablishment of the splenic red-pulp macrophage compartment, and restoration of iron homeostasis. In fact, the currently available evidence supports a model in which recruitment of monocytes is linked to proliferation of previously recruited monocyte-derived macrophages (Randolph, 2013). Turnover of epidermal Langerhans cells. Bethesda, MD 20894, Web Policies In the outer layer of the marginal zone, marginal zone macrophages express abundant select scavenger and pattern recognition receptors104-107, such as CD204 (Scavenger receptor A), MARCO (Macrophage receptor with collagenous structure) and CD209b (SIGN-R1, a DC-SIGN homologue), and are well placed microanatomically to capture blood-borne antigens47, 101, 102, 104. Until the demonstration that proliferation of macrophages could solely account for macrophage expansion at sites of nematode infection, macrophage proliferation was not recognized as a powerful modifier of macrophage numbers within organs. Critically, the factors that regulate the autonomous cell survival and/or the proliferative renewal of macrophages are beginning to be identified and characterized. Dupasquier M, et al. Costa M, da Costa V, Lores P, Landeira M, Rodrguez-Zraquia SA, Festari MF, Freire T. Sci Rep. 2022 Oct 21;12(1):17661. doi: 10.1038/s41598-022-21520-w. Beach C, MacLean D, Majorova D, Arnold JN, Olcina MM. Tauber AI. In the context of the TH2 environment associated with parasite infection, substantial IL-4-dependent proliferation can expand tissue resident macrophage numbers beyond that normally seen within the tissue. Local macrophage proliferation correlates with increased renal M-CSF expression in human glomerulonephritis. It will be critical to assess what roles these different growth factors play not only in the proliferation and/or survival of tissue-resident macrophages, but also in the local definition of their tissue-specific phenotypes and functions. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. Before Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F, Vyssotski AL, Bifone A, Gozzi A, Ragozzino D, Gross CT. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Deconvoluting the ontogeny of hematopoietic stem cells. doi: 10.1084/jem.162.3.993. Tissue-resident macrophages were regarded as differentiated monocytes, which seed the tissues to perform immune sentinel and homeostatic functions. While they may seem unrelated, these habits can make your mouth susceptible to periodontitis and tooth loss. Haemopoietic stem cells (HSC) associate with mesenchymal stromal cells in a specialised niche in the bone marrow during the early stages of haemopoiesis. Synaptic pruning by microglia is necessary for normal brain development. Ueno M, Fujita Y, Tanaka T, Nakamura Y, Kikuta J, Ishii M, Yamashita T. Layer V cortical neurons require microglial support for survival during postnatal development. Nat Rev Neurosci. These are long lived cells. Author manuscript; available in PMC 2015 Jun 17. Macrophages (also known as leucocytes) are specialized white blood cells of the immune system and play a vital part in innate (inborn) immunity and immune responses of the body. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, et al. Their importance in iron processing is evident from the study of Spi-C-deficient mice103. [These studies demonstrate the early-embryonic origins of adult microglia, which are maintained throughout life by local self-renewal (see. Antoniades CG, et al. Lauder SN, et al. Macrophages have many origins. Wake H, Moorhouse AJ, Miyamoto A, Nabekura J. Microglia: actively surveying and shaping neuronal circuit structure and function. Ganz T. Macrophages and systemic iron homeostasis. Immunol Rev. GATA6 can be induced by vitamin A signaling, but addition of vitamin A to cultured macrophages will induce GATA6 only when sources of fetal macrophages, such as fetal-liver macrophages, are used (Okabe and Medzhitov, 2014). Understanding the role of monocytes and microglia in neurocognitive dysfunction is challenging because subtle dysfunctions might not be readily detectable. Marginal zone and metallophilic macrophages (indicated immunohistochemically by SIGNR1 (blue, bottom) and CD169 (green) expression respectively) play roles in the capture of microbes and viruses from the circulation. An official website of the United States government. 173. For example, . Henson PM, Hume DA. Utilizing the Cx3cr1CreER system, a recent study has demonstrated that specific deletion of the kinase TAK1 in microglia (and not infiltrating monocytes) prevents both initial and relapsing paralysis, as well as inhibition of cellular expansion and disease progression (Goldmann et al., 2013). Few studies have examined whether human tissue macrophages are similarly composed of resident embryonically derived and monocyte-derived macrophage subsets. ASSIGNMENT NO.3 TOPIC TISSUE MACROPHAGES OF ALL PARTS OF THE Study Resources Mantovani A, Sica A, Locati M. Macrophage polarization comes of age. Connective Tissues. Where are macrophages found in connective tissue? Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. These data indicate that forced ontological reprogramming of tissue macrophages can be easily achieved with clodronate-liposome-mediated depletion strategies in these organs. PMC legacy view In this capacity, they patrol extravascular tissues to pick up antigens for transport to draining lymph nodes, all the while remaining relatively undifferentiated rather than committing to macrophages or DCs (Jakubzick et al., 2013). Other tissues may be similarly seeded or established after definitive hematopoiesis in the fetal liver or bone marrow. Embryonically derived fetal monocytes appear to colonize the lung shortly after birth and differentiate into alveolar macrophages in a GM-CSF-dependent process (Guilliams et al., 2013). At the very least, one may expect that the requirement for the mature prenatal derived cells to exist in a seemingly quiescent state and yet remain competent to proliferate as a mature cell (during homeostasis or inflammation) must be under defined transcriptional control. Yona S, et al. The liver is the best characterized adult organ capable of regeneration in mammals after injury or resection. Comparison of gene expression profiles between human and mouse monocyte subsets. The evolution of adaptive immune systems. These large immune cells are present in nearly all tissues and actively . In the last decade, it has been revealed that many . This represents a general limitation of Cre-dependent lineage-tracing systems. Some of the more important tissue macrophages are: Kupffer cells in the liver sinusoids, microglial cells in the brain, alveolar macrophages, dendritic cells in the skin, macrophages in lymphoid tissue and mammary macrophages (Bielefeldt Ohmann and Babiuk, 1986; Bryan et al., 1988 ). Lucas T, et al. In this section, we will highlight the relevant studies that allow us to discern how different tissue macrophage populations change during times of stress, whether functions possessed by macrophages during embryonic development are hard wired and therefore retained by their adult progeny, and how macrophages are conditioned by the tissue in which they reside. Immune checkpoint therapy (ICT) is among the widely used treatments for breast cancer (BC), but most patients do not respond to ICT and the availability of the predictive biomarkers is limited. These data provide further evidence that local signaling within tissues might be sufficient to promote the acquisition of specialized macrophage functions irrespective of the ontological lineage (Haldar et al., 2014). Dioszeghy V, et al. Damaged or senescent erythrocytes that display altered surface membranes are phagocytosed and proteolytically degraded by macrophages, which release hemoglobin and ultimately iron that is stored as ferritin complexes or exported via ferroportin91. J Exp Med. Differential roles of macrophages in diverse phases of skin repair. These mutant mice exhibit a very specific absence of splenic red pulp macrophages, and thus impaired clearance of erythrocytes and a build up of iron in the red pulp. Studies that focus on the role of monocyte-derived macrophages invariably target the CCR2 pathway, which also limits monocyte egress from the bone marrow during steady state. 84), which may further regulate these clearance processes. Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans. Malur A, Baker AD, McCoy AJ, Wells G, Barna BP, Kavuru MS, Malur AG, Thomassen MJ. The molecular basis of pulmonary alveolar proteinosis. Si Y, Tsou CL, Croft K., and Charo, I.F. During brain ischemia, microglia significantly increase the duration of their interactions with synapses, which correlates with the loss of dysfunctional synaptic structures and suggests that microglia serve an early protective role after brain injury (Wake et al., 2009). Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR, 3rd, Lafaille JJ, Hempstead BL, Littman DR, Gan WB. Yoshida H, et al. This scenario results in abundant production of interferon- (IFN-), which leads a feedback inhibition process that interrupts erythropoiesis. after experimental whole body irradiation)18, 30. The Nuclear Receptor LXR controls the functional specialization of splenic macrophages. Macrophages and dendritic cells use different Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells. Tissue-resident macrophages: then and now. Several detailed review articles describing different aspects of macrophage ontogeny and function have been published (Sieweke and Allen, 2013; Davies et al., 2013a; Wynn et al., 2013). Scar tissue is the most common reason that Carpal Tunnel Symptoms, such as hand numbness, hand pain and wrist pain gets worse after surgery than before surgery. Osteoclasts are terminally differentiated macrophage-derived cells with specialized functions in bone remodeling. the display of certain parts of an article in other eReaders. After injury, liver macrophages engulf hepatocyte debris and activate a program leading to the secretion of WNT ligands, which direct hepatocyte differentiation from progenitors (You et al., 2013; Boulter et al., 2012). A quantifiable proliferative burst of tissue macrophages restores homeostatic macrophage populations after acute inflammation. Disclaimer, National Library of Medicine Both have various types of PRRs, both have the powerful mechanism of phagocytosis, However, tissue-resident macrophages are not a homogeneous population, but are in fact a grouping of cells with similar functions and phenotypes. Initial fate-mapping studies of adult macrophages were focused on microglia and Langerhans cells. The consequence of this restricted 12/15-lipoxygenase expression is to effectively create a sorting system for apoptotic cells that promotes their clearance by tissue-resident and not inflammatory bone marrow-derived macrophages. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Mice deficient in PU.1, CSF1R, or M-CSF (CSF1) lack many tissue macrophages from the earliest stages of development beginning at the time of yolk sac hematopoiesis. Tissue-resident macrophages are a heterogeneous population of immune cells that fulfill tissue-specific and niche-specific functions. This limited hematopoietic cell diversity is reminiscent of the Drosophila immune system (Makhijani and Bruckner, 2012) and indicative of the conserved origin of the yolk-sac-derived macrophage lineage. The macrophages (M) of the spleen are shown in their distinct anatomical locations. During development, erythromyeloid progenitors from yolk sac and foetal liver give rise to tissue-resident macrophages which persist during adult life as long-lived cells of widely varying mophology that turn over locally. doi: 10.1038/nri3789. Tissues use resident dendritic cells and macrophages to maintain homeostasis and to regain homeostasis upon tissue injury: the immunoregulatory role of changing tissue environments. 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