Local Macrophage Proliferation, Rather than Recruitment from the Blood, Is a Signature of T
            <sub>H</sub>
            2 Inflammation

Jenkins, Stephen J.; Rückerl, Dominik; Cook, Peter C.; Jones, Lucy; Finkelman, Fred D.; Rooijen, Nico van; MacDonald, Andrew S.; Allen, Judith E.

doi:10.1126/science.1204351

Cited by 1,229 publications

(1,306 citation statements)

References 35 publications

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“…In mice, tissue macrophages have been shown to proliferate in response to IL-4 produced in type 2 helper T-cell immune responses. 85 Although historically macrophages are not thought to divide in humans and nonhuman primates, the local microenvironment in SIVE or HIVE may support proliferation of CD163 þ macrophages. Another possibility is that CD163 þ macrophages are recruited to the perivascular space and SIVE lesions from sites other than the bone marrow.…”

Section: Mac387 þ Macrophages Do Not Appear To Differentiate Into Cd1mentioning

confidence: 99%

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

Nowlin

Burdo

Midkiff

et al. 2015

The American Journal of Pathology

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Macrophage recruitment to the central nervous system (CNS) during AIDS pathogenesis is poorly understood. We measured the accumulation of brain perivascular (CD163 þ ) and inflammatory (MAC387 þ ) macrophages in SIV-infected monkeys. Monocyte progenitors were 5-bromo-2 0 -deoxyuridine (BrdU) labeled in bone marrow, and CNS macrophages were labeled serially with fluorescent dextrans injected into the cisterna magna. MAC387 þ macrophages accumulated in the meninges and choroid plexus in early inflammation and in the perivascular space and SIV encephalitis (SIVE) lesions late. CD163 þ macrophages accumulated in the perivascular space and SIVE lesions with late inflammation. Most of the BrdU þ cells were MAC387 þ ; however, CD163 þ BrdU þ macrophages were present in the meninges and choroid plexus with AIDS. Most (81.6% AE 1.8%) of macrophages in SIVE lesions were present in the CNS before SIVE lesion formation. There was a 2.9-fold increase in SIVp28 þ macrophages entering the CNS late compared with those entering early (P < 0.05). The rate of CD163 þ macrophage recruitment to the CNS inversely correlated with time to death (P < 0.03) and increased with SIVE. In SIVE animals, soluble CD163 correlated with CD163 þ macrophage recruitment (P Z 0.02). Most perivascular macrophages that comprise SIVE lesions and multinucleated giant cells are present in the CNS early, before SIVE lesions are formed. Most SIV-infected macrophages traffic to the CNS terminally with AIDS.

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Section: Mac387 þ Macrophages Do Not Appear To Differentiate Into Cd1mentioning

confidence: 99%

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

Nowlin

Burdo

Midkiff

et al. 2015

The American Journal of Pathology

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“…Moreover, in a mouse model of type II inflammation using nematode infection, local IL-4-dependent macrophage proliferation is shown to be a key determinant of the numbers of M2-polarized macrophages in the lung [21]. In the same vein, a recent paper in this Journal by Taylor and colleagues demonstrates that macrophage accumulation in the inflamed peritoneum depends on macrophage proliferation [22].…”

Section: Tam Accumulationmentioning

confidence: 97%

Cancer‐promoting tumor‐associated macrophages: New vistas and open questions

et al. 2011

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Tumor‐associated macrophages (TAMs) are key components of the tumor macroenvironment. Cancer‐ and host cell‐derived signals generally drive the functions of TAMs towards an M2‐like polarized, tumor‐propelling mode; however, when appropriately re‐educated. TAMs also have the potential to elicit tumor destructive reactions. Here, we discuss recent advances regarding the immunobiology of TAMs and highlight open questions including the mechanisms of their accumulation (recruitment versus proliferation), their diversity and how to best therapeutically target these cells.

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“…17,18 The mechanism underlying this process is not clear, although PI3K/AKT signaling has been implicated. 16 Here we show that (i) in vitro, the low, basal level of p53 activity in IL4-polarized M2 macrophages is associated with significant cell proliferation and that loss of p53 potentiates, whereas pharmacological activation of p53 impairs M2-mediated proliferation, and (ii) in vivo, IL4 stimulation increased peritoneal macrophage cellularity, which was more marked in the absence of p53.…”

Section: Figure 7 (Continued)mentioning

confidence: 99%

A unique role for p53 in the regulation of M2 macrophage polarization

Li¹,

et al. 2014

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P53 is critically important in preventing oncogenesis but its role in inflammation in general and in the function of inflammatory macrophages in particular is not clear. Here, we show that bone marrow-derived macrophages exhibit endogenous p53 activity, which is increased when macrophages are polarized to the M2 (alternatively activated macrophage) subtype. This leads to reduced expression of M2 genes. Nutlin-3a, which destabilizes the p53/MDM2 (mouse double minute 2 homolog) complex, promotes p53 activation and further downregulates M2 gene expression. In contrast, increased expression of M2 genes was apparent in M2-polarized macrophages from p53-deficient and p53 mutant mice. Furthermore, we show, in mice, that p53 also regulates M2 polarization in peritoneal macrophages from interleukin-4-challenged animals and that nutlin-3a retards the development of tolerance to Escherichia coli lipopolysaccharide. P53 acts via transcriptional repression of expression of c-Myc (v-myc avian myelocytomatosis viral oncogene homolog) gene by directly associating with its promoter. These data establish a role for the p53/MDM2/c-MYC axis as a physiological 'brake' to the M2 polarization process. This work reveals a hitherto unknown role for p53 in macrophages, provides further insight into the complexities of macrophage plasticity and raises the possibility that p53-activating drugs, many of which are currently being trialled clinically, may have unforeseen effects on macrophage function. Macrophages have key roles in the response to stress, injury, infection and inflammation. The M1 (classically activated macrophages) are induced by lipopolysaccharide (LPS) and cytokines such as interferon-γ (IFNγ) and characterized by the expression of a wide range of proinflammatory genes. M2 (alternatively activated macrophages) are induced by T helper type 2 (Th2) cytokines such as interleukin-4 (IL4) and IL13 and express high levels of anti-inflammatory and tissue repair marker genes. M2 macrophages perform immunoregulatory functions including defense against infection, promotion of angiogenesis and wound healing. 1 Macrophages exist on a continuum between M1 and M2 subtypes undergoing dynamic changes between these different functional states depending on changes in their microenvironment. This 'plasticity' involves extensive changes in macrophage gene sets and provides the potential to develop drugs to manipulate the macrophage subtype. 2 As such, macrophage polarization, and its molecular basis, has been vigorously researched in recent years.P53 has a crucial role in cancer by controlling the expression of genes involved in apoptosis, cell cycle arrest, metabolism and DNA repair. 3 While inflammation is increasingly recognized as a factor in determining the predisposition to cancer, 4 the role of p53 in inflammation is not clear. Macrophages from p53 − / − mice produce increased quantities of proinflammatory cytokines in response to LPS, 5 while peritoneal macrophage count and susceptibility to lethal septic shock are increased in p53 − ...

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Local Macrophage Proliferation, Rather than Recruitment from the Blood, Is a Signature of T _H 2 Inflammation

Cited by 1,229 publications

References 35 publications

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

Cancer‐promoting tumor‐associated macrophages: New vistas and open questions

A unique role for p53 in the regulation of M2 macrophage polarization

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Local Macrophage Proliferation, Rather than Recruitment from the Blood, Is a Signature of T H 2 Inflammation

Cited by 1,229 publications

References 35 publications

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

Cancer‐promoting tumor‐associated macrophages: New vistas and open questions

A unique role for p53 in the regulation of M2 macrophage polarization

Contact Info

Product

Resources

About

Local Macrophage Proliferation, Rather than Recruitment from the Blood, Is a Signature of T _H 2 Inflammation