The role of α4 and LFA-1 integrins in selectin-independent monocyte and neutrophil migration to joints of rats with adjuvant arthritis

Birner, Ulrieke; Issekutz, Thomas B.; Walter, Ulrike; Issekutz, Andrew C.

doi:10.1093/intimm/12.2.141

Cited by 20 publications

(16 citation statements)

References 33 publications

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“…Recruitment of leukocytes into the inflamed joint is a multistep process that involves complex interactions between adhesion molecules expressed by the invading cells and the inflamed tissue. Even though this recruitment involves multiple classes of adhesion molecules, previous studies have demonstrated a crucial role for LFA-1 in this process (52,53). The effect of anti-LFA-1 inhibitors in the development and progression of inflammatory arthritis in this model further supports these findings.…”

Section: Discussionsupporting

confidence: 82%

An LFA-1 (αLβ2) Small-Molecule Antagonist Reduces Inflammation and Joint Destruction in Murine Models of Arthritis

Suchard

Stetsko

Davis

et al. 2010

The Journal of Immunology

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LFA-1 appears to play a central role in normal immune responses to foreign Ags. In autoimmune or inflammatory diseases, there is increased expression of LFA-1 and/or its counterligand, ICAM-1. Others have demonstrated that the targeted disruption of LFA-1:ICAM interactions, either by gene deletion or Ab treatment in mice, results in reduced leukocyte trafficking, inflammatory responses, and inhibition of inflammatory arthritis in the K/BxN serum transfer model. However, there has been little success in finding a small-molecule LFA-1 antagonist that can similarly impact rodent models of arthritis. In this paper, we present the first reported example of an LFA-1 small-molecule antagonist, BMS-587101, that is efficacious in preclinical disease models. In vitro, BMS-587101 inhibited LFA-1–mediated adhesion of T cells to endothelial cells, T cell proliferation, and Th1 cytokine production. Because BMS-587101 exhibits in vitro potency, cross-reactivity, and oral bioavailability in rodents, we evaluated the impact of oral administration of this compound in two different models of arthritis: Ab-induced arthritis and collagen-induced arthritis. Significant impact of BMS-587101 on clinical score in both models was observed, with inhibition comparable or better than anti-mouse LFA-1 Ab. In addition, BMS-587101 significantly reduced cytokine mRNA levels in the joints of Ab-induced arthritis animals as compared with those receiving vehicle alone. In paws taken from the collagen-induced arthritis study, the bones of vehicle-treated mice had extensive inflammation and bone destruction, whereas treatment with BMS-587101 resulted in marked protection. These findings support the potential use of an LFA-1 small-molecule antagonist in rheumatoid arthritis, with the capacity for disease modification.

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Section: Discussionsupporting

confidence: 82%

An LFA-1 (αLβ2) Small-Molecule Antagonist Reduces Inflammation and Joint Destruction in Murine Models of Arthritis

Suchard

Stetsko

Davis

et al. 2010

The Journal of Immunology

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“…22 Multiple recent examples have shown that ␣ 4 /ligand interactions can contribute not only to firm adhesion and migration of mature leukocytes, but also to their tethering/rolling. [47][48][49][50][51][52][53][54] Thus, an additional function of ␣ 4 , which has been overlooked previously, is projected in recent studies, showing ␣ 4 -mediated tethering and/or rolling of leukocytes both in vitro and in vivo. Our previous data 3 showing decreased homing of normal donor cells treated with anti-␣ 4 did not directly address the particular stage of involvement (initial capture, firm adhesion/ migration) of ␣ 4 -integrin in progenitor cell homing.…”

Section: Discussionmentioning

confidence: 99%

Molecular pathways in bone marrow homing: dominant role of α4β1 over β2-integrins and selectins

Papayannopoulou

Priestley

Nakamoto

et al. 2001

Blood

176

156

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The specific retention of intravenously administered hemopoietic cells within bone marrow is a complex multistep process. Despite recent insights, the molecular mechanics governing this process remain largely undefined. This study explored the influence of ␤ 2 -integrins on the homing to bone marrow and repopulation kinetics of progenitor cells. Both antifunctional antibodies and genetically deficient cells were used. In addition, triple selectin-deficient mice were used as recipients of either deficient (selectin or ␤ 2 ) or normal cells in homing experiments. The homing patterns of either ␤ 2 null or selectin null cells into normal or selectin-deficient recipients were similar to those of normal cells given to normal recipients. Furthermore, spleen colonyforming units and the early bone marrow repopulating activity for the first 2 weeks after transplantation were not significantly different from those of control cells. These data are in contrast to the importance of ␤ 2 -integrin and selectins in the adhesion/migration cascade of mature leukocytes. The special bone marrow flow hemodynamics may account for these differences. Although early deaths after transplantation can be seen in recipients deficient in CD18 and selectin, these are attributed to septic complications rather than homing defects. However, when ␤ 2 -or selectin-null donor cells are treated with anti-␣ 4 antibodies before their transplantation to normal or selectin-deficient recipients, a dramatic inhibition of homing (>90%) was found. The data suggest that the ␣ 4 ␤ 1 /vascular cell adhesion molecule-1 pathway alone is capable of providing effective capture of cells within the bone marrow, but if its function is compromised, the synergistic contribution of other pathways, that is, ␤ 2 -integrins or selectins, is uncovered. IntroductionRestriction of the developing hemopoietic cells to certain anatomic sites within the body, that is, the extravascular spaces of the bone marrow (BM), signifies a unique microenvironment capable of providing not only anchorage to hemopoietic cells, but of transmitting signals enabling their proliferation and differentiation. The relationship of hemopoietic cells with their microenvironment is a highly dynamic one allowing further expansion on demand and, depending on the stimuli, the movement of cells in and out of their microenvironment. The ability of intravenously administered cells to re-establish connections within the BM environment is a clinically exploited example of that flexibility. As the sinusoidal endothelial cells separate the extravascular space from the circulation, intravenously administered cells need first to tether to the sinusoidal endothelium, then to firmly anchor themselves within the extravascular space through reversible adhesion and transmigration steps. Although several insights regarding the molecular pathways that guide these processes have been obtained, our knowledge of this complex process remains incomplete. Early reports suggest that galactose-and mannose-specific lectins (present...

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“…P-selectin can be expressed on high endothelial venules in PP and up-regulated during inflammation (66), and its ligand PSGL-1 is expressed by both monocytes and neutrophils (67). In the absence of MAdCAM-1, Pselectin could thus play a role in the recruitment of monocytes and neutrophils to PP during infection (67,68).…”

Section: Discussionmentioning

confidence: 99%

Monocyte Recruitment, Activation, and Function in the Gut-Associated Lymphoid Tissue during Oral Salmonella Infection

Rydström

Wick

2007

The Journal of Immunology

126

198

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Neutrophils, monocytes, and dendritic cells (DC) are phenotypically and functionally related phagocytes whose presence in infected tissues is critical to host survival. Their overlapping expression pattern of surface molecules, the differentiation capacity of monocytes, and the presence of monocyte subsets underscores the complexity of understanding the role of these cells during infection. In this study we use five- to seven-color flow cytometry to assess the phenotype and function of monocytes recruited to Peyer’s patches (PP) and mesenteric lymph nodes (MLN) after oral Salmonella infection of mice. The data show that CD68highGr-1int (intermediate) monocytes, along with CD68intGr-1high neutrophils, rapidly accumulate in PP and MLN. The monocytes have increased MHC-II and costimulatory molecule expression and, in contrast to neutrophils and DC, produce inducible NO synthase. Although neutrophils and monocytes from infected mice produce TNF-α and IL-1β upon ex vivo culture, DC do not. In addition, although recruited monocytes internalize Salmonella in vitro and in vivo they did not induce the proliferation of OT-II CD4+ T cells after coincubation with Salmonella expressing OVA despite their ability to activate OT-II cells when pulsed with the OVA323–339 peptide. We also show that recruited monocytes enter the PP of infected mice independently of the mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Finally, recruited but not resident monocytes increase in the blood of orally infected mice, and MHC-II up-regulation, but not TNF-α or iNOS production, occur already in the blood. These studies are the first to describe the accumulation and function of monocyte subsets in the blood and GALT during oral Salmonella infection.

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The role of α4 and LFA-1 integrins in selectin-independent monocyte and neutrophil migration to joints of rats with adjuvant arthritis

Cited by 20 publications

References 33 publications

An LFA-1 (αLβ2) Small-Molecule Antagonist Reduces Inflammation and Joint Destruction in Murine Models of Arthritis

An LFA-1 (αLβ2) Small-Molecule Antagonist Reduces Inflammation and Joint Destruction in Murine Models of Arthritis

Molecular pathways in bone marrow homing: dominant role of α4β1 over β2-integrins and selectins

Monocyte Recruitment, Activation, and Function in the Gut-Associated Lymphoid Tissue during Oral Salmonella Infection

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