Fas Death Receptor Signaling Represses Monocyte Numbers and Macrophage Activation In Vivo

Brown, Nicholas K.; Hutcheson, Jack; Bickel, Emily; Scatizzi, John C.; Albee, Lee D.; Haines, G. Kenneth; Eslick, Joy; Bradley, Kathleen; Taricone, Elsa; Perlman, Harris

doi:10.4049/jimmunol.173.12.7584

Cited by 36 publications

(9 citation statements)

References 57 publications

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“…The CD11b lineage was examined in peripheral blood using the markers 7/4, CD62L and Gr1 recognizing Neutrophil 7/4 antigen (Neu7/4), L-selectin and Ly6C/Ly6G respectively, in accordance with previous characterizations[37-39]. Peripheral PMNs were Gr1 +++ , highly granular, CD62L + and were Neu7/4 -/+ (gate 1, Fig 5A).…”

Section: Resultssupporting

confidence: 53%

Systemic IFN‐α drives kidney nephritis in B6.Sle123 mice

Fairhurst

Mathian

Connolly³

et al. 2008

Eur J Immunol

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The impact of IFN-a secretion on disease progression was assessed by comparing phenotypic changes in the lupus-prone B6.Sle1Sle2Sle3 (B6.Sle123) strain and the parental C57BL/6 (B6) congenic partner using an adenovirus (ADV) expression vector containing a recombinant IFN-a gene cassette (IFN-ADV). A comprehensive comparison of cell lineage composition and activation in young B6 and B6.Sle123 mice revealed a variety of cellular alterations in the presence and absence of systemic IFN-a. Most IFN-a-induced phenotypes were similar in B6 and B6.Sle123 mice; however, B6.Sle123 mice uniquely exhibited increased B1 and plasma cells after IFN-a exposure, although both strains had an overall loss of mature B cells in the bone marrow, spleen and periphery. Although most of the cellular effects of IFN-a were identical in both strains, severe glomerulonephritis occurred only in B6.Sle123 mice. Mice injected with IFN-ADV showed an increase in immune complex deposition in the kidney, together with an unexpected decrease in serum anti-nuclear antibody levels. In summary, the predominant impact of systemic IFN-a in this murine model is an exacerbation of mechanisms mediating end organ damage.

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Section: Resultssupporting

confidence: 53%

Systemic IFN‐α drives kidney nephritis in B6.Sle123 mice

Fairhurst

Mathian

Connolly³

et al. 2008

Eur J Immunol

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“…Activated macrophages release Fas ligand, and are also capable of undergoing Fas-mediated death in certain circumstances (31,32). Immature monocytes are also susceptible to Fas-mediated death (33), and this susceptibility might be retained in many of the macrophages in the toxoplasmic exudate, since our data imply that these cells are predominantly recent emigrants. In addition, macrophages can release a variety of other mediators capable of triggering apoptosis, including reactive oxygen and nitrogen species.…”

Section: Discussionmentioning

confidence: 73%

Externally Triggered Egress Is the Major Fate of Toxoplasma gondii during Acute Infection

Tomita¹,

Yamada²,

Weiss

et al. 2009

The Journal of Immunology

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The apicomplexan parasite Toxoplasma gondii expands during acute infection via a cycle of invasion, intracellular replication, and lytic egress. Physiological regulation has not yet been demonstrated for either invasion or egress. We now report that, in contrast to cell culture systems, in which egress occurs only after five or more parasite divisions (2–3 days), intracellular residence is strikingly abbreviated in inflammatory cells in vivo, and early egress (after zero to two divisions) is the dominant parasite fate in acutely infected mice. Adoptive transfer experiments demonstrate rapid, reciprocal, kinetically uniform parasite transfer between donor and recipient compartments, with a t1/2 of ∼3 h. Inflammatory macrophages are major participants in this cycle of lytic egress and reinfection, which drives rapid macrophage turnover. Inflammatory triggering cells, principally macrophages, elicit egress in infected target macrophages, a process we term externally triggered egress (ETE). The mechanism of ETE does not require reactive oxygen or nitrogen species, the mitochondrial permeability transition pore, or a variety of signal transduction mediators, but is dependent on intracellular calcium and is highly sensitive to SB203580, an inhibitor of p38 MAPK as well as a related parasite-encoded kinase. SB203580 both inhibited the initiation of ETE and altered the progression of egress. Parasites recently completing a cycle of egress and reinfection were preferentially restricted in vivo, supporting a model in which ETE may favor host defense by a process of haven disruption. ETE represents a novel example of interaction between a parasite infectious cycle and host microenvironment.

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“…While, we previously obtained opposing data with regard to the role of p21 in the development of K/BxN serum transfer-induced arthritis, these differences are attributable to the mouse background. After extensive phenotyping of the mice, we uncovered that p21 −/− mice on a mixed background, but not on an inbred background, develop significantly less inflammatory monocytes when compared to controls or even mice (op/op) lacking macrophage colony stimulating factor (M-CSF) (11, 32). Further, injection of Wt macrophages into p21 −/− mice restores their susceptibility to inflammatory arthritis (11).…”

Section: Discussionmentioning

confidence: 99%

Cyclin‐dependent kinase inhibitor p21, via its C‐terminal domain, is essential for resolution of murine inflammatory arthritis

Mavers¹,

Cuda²,

Misharin³

et al. 2011

Arthritis & Rheumatism

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Objective The mechanism responsible for persistent inflammation of the synovium that occurs in patients with rheumatoid arthritis (RA) is unknown. Previously, we were the first to demonstrate that expression of the cyclin dependent kinase (CDK) inhibitor p21(WAF1/CIP1) is reduced in synovial tissue from RA patients compared to osteoarthritis patients and that p21 is a novel suppressor of the inflammatory response in macrophages. Here, we sought to determine the role and mechanism of p21-mediated suppression of experimental inflammatory arthritis. Methods Experimental arthritis was induced in WT or p21−/− (C57BL/6) mice using the K/BxN serum transfer induced model. p21-peptide mimetics were administered to mice as a prophylactic for arthritis development. LPS-induced cytokine and signal transduction pathways were examined in macrophages that were treated with p21-peptide mimetics using Luminex-based assays, flow cytometry, or ELISAs. Results p21−/− mice exhibit enhanced and sustained development of experimental inflammatory arthritis, which is associated with markedly increased numbers of macrophages and severe articular destruction. Administration of a p21-peptide mimetic suppresses activation of macrophages and reduces the severity of experimental arthritis only in p21-intact mice. Mechanistically, treatment with the p21-peptide mimetic leads to activation of the serine/threonine kinase Akt and subsequent reduction in the activated isoform of mitogen-activated protein kinase p38 in macrophages. Conclusion These data are the first to reveal that p21 plays an important role in limiting the activation response of macrophages in an inflammatory disease such as RA. Thus, targeting p21 in macrophages may be crucial for suppressing the development and persistence of RA.

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Fas Death Receptor Signaling Represses Monocyte Numbers and Macrophage Activation In Vivo

Cited by 36 publications

References 57 publications

Systemic IFN‐α drives kidney nephritis in B6.Sle123 mice

Systemic IFN‐α drives kidney nephritis in B6.Sle123 mice

Externally Triggered Egress Is the Major Fate of Toxoplasma gondii during Acute Infection

Cyclin‐dependent kinase inhibitor p21, via its C‐terminal domain, is essential for resolution of murine inflammatory arthritis

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