C5a receptor enables participation of mast cells in immune complex arthritis independently of Fcγ receptor modulation

Nigrović, Peter A.; Malbec, Odile; Liu, Bao; Markiewski, Maciej M.; Kepley, Chris; Gerard, Norma P.; Gérard, Craig; Daëron, Marc; Lee, David M.

doi:10.1002/art.27659

Cited by 39 publications

(38 citation statements)

References 51 publications

(86 reference statements)

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“…17,49 Our findings are complementary to this report. Indeed, we found that this initial event is independent of the presence of platelets and expression of SERT (supplemental Figure 4A-B).…”

supporting

confidence: 86%

Platelets can enhance vascular permeability

Cloutier

Paré

Farndale

et al. 2012

Blood

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205

162

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AbstractPlatelets survey blood vessels, searching for endothelial damage and preventing loss of vascular integrity. However, there are circumstances where vascular permeability increases, suggesting that platelets sometimes fail to fulfill their expected function. Human inflammatory arthritis is associated with tissue edema attributed to enhanced permeability of the synovial microvasculature. Murine studies have suggested that such vascular leak facilitates entry of autoantibodies and may thereby promote joint inflammation. Whereas platelets typically help to promote microvascular integrity, we examined the role of platelets in synovial vascular permeability in murine experimental arthritis. Using an in vivo model of autoimmune arthritis, we confirmed the presence of endothelial gaps in inflamed synovium. Surprisingly, permeability in the inflamed joints was abrogated if the platelets were absent. This effect was mediated by platelet serotonin accumulated via the serotonin transporter and could be antagonized using serotonin-specific reuptake inhibitor antidepressants. As opposed to the conventional role of platelets to microvascular leakage, this demonstration that platelets are capable of amplifying and maintaining permeability adds to the rapidly growing list of unexpected functions for platelets.

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supporting

confidence: 86%

Platelets can enhance vascular permeability

Cloutier

Paré

Farndale

et al. 2012

Blood

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205

162

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“…WT and RasGRP4-null mice had a similar initial serum-induced flare reaction (Fig. 5A), which is an acute transient tissue edema dependent on MCs and neutrophils (19). Despite these data, RasGRP4-null mice remained essentially arthritis-free in the 10-day experiments (Fig.…”

Section: Rasgrp4 Contributes To Maximal Inflammation In Acute Dss-indmentioning

confidence: 84%

“…To induce arthritis, each mouse received 75 l of K/BxN mouse serum intraperitoneally diluted to a final volume of 150 l with LPS-free PBS on experimental days 0 and 2. Before and 30 min after the initial injection, paw swelling was measured using a spring-loaded caliper as described (19) to measure acute edema ("flare") reflective of MC activation, among other factors. Thereafter, clinical indices were recorded at 48-h intervals and graded on a scale of 0 -12.…”

Section: Targeting Of Rasgrp4 Locus In Mouse Embryonic Stem (Es) Cellmentioning

confidence: 99%

Ras Guanine Nucleotide-releasing Protein-4 (RasGRP4) Involvement in Experimental Arthritis and Colitis

Adachi

Krilis

Nigrović

et al. 2012

Journal of Biological Chemistry

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Background: Mast cells express RasGRP4, which is a guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor. Results: A RasGRP4-null C57BL/6 mouse line was created to evaluate the importance of this signaling protein. Conclusion:RasGRP4 participates in experimental colitis and arthritis. Significance: The inactivation of RasGRP4 might be of therapeutic benefit in some inflammatory diseases.

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“…S7). Mast cells were suggested to play an essential role in the K/BxN model of autoantibody-induced arthritis, and C5aR and FcγRIII on mast cells as well as mast cell-derived IL-1β were considered to significantly contribute to arthritis (28,(36)(37)(38). However, we found that C5aR and FcγRIII on radiosensitive cells alone are completely sufficient for arthritis and that Kit w /Kit w-v → C5ar −/− and Kit w /Kit w-v → Fcgr3 −/− chimeric mice were also fully susceptible to arthritis, demonstrating that C5aR and FcγRIII on mast cells do not contribute significantly to arthritis in the K/BxN model.…”

Section: Discussionmentioning

confidence: 99%

Neutrophils orchestrate their own recruitment in murine arthritis through C5aR and FcγR signaling

Sadik

Kim

Iwakura

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

126

112

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Neutrophil recruitment into the joint is a hallmark of inflammatory arthritides, including rheumatoid arthritis (RA). In a mouse model of autoantibody-induced inflammatory arthritis, neutrophils infiltrate the joint via multiple chemoattractant receptors, including the leukotriene B 4 (LTB 4 ) receptor BLT1 and the chemokine receptors CCR1 and CXCR2. Once in the joint, neutrophils perpetuate their own recruitment by releasing LTB 4 and IL-1β, presumably after activation by immune complexes deposited on joint structures. Two pathways by which immune complexes may activate neutrophils include complement fixation, resulting in the generation of C5a, and direct engagement of Fcγ receptors (FcγRs). Previous investigations showed that this model of autoantibody-induced arthritis requires the C5a receptor C5aR and FcγRs, but the simultaneous necessity for both pathways was not understood. Here we show that C5aR and FcγRs work in sequence to initiate and sustain neutrophil recruitment in vivo. Specifically, C5aR activation of neutrophils is required for LTB 4 release and early neutrophil recruitment into the joint, whereas FcγR engagement upon neutrophils induces IL-1β release and subsequent neutrophil-active chemokine production, ensuring continued inflammation. These findings support the concept that immune complex-mediated leukocyte activation is not composed of overlapping and redundant pathways, but that each element serves a distinct and critical function in vivo, culminating in tissue inflammation.

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C5a receptor enables participation of mast cells in immune complex arthritis independently of Fcγ receptor modulation

Cited by 39 publications

References 51 publications

Platelets can enhance vascular permeability

Platelets can enhance vascular permeability

Ras Guanine Nucleotide-releasing Protein-4 (RasGRP4) Involvement in Experimental Arthritis and Colitis

Neutrophils orchestrate their own recruitment in murine arthritis through C5aR and FcγR signaling

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