Limits...
Novel biphasic role for lymphocytes revealed during resolving inflammation.

Rajakariar R, Lawrence T, Bystrom J, Hilliard M, Colville-Nash P, Bellingan G, Fitzgerald D, Yaqoob MM, Gilroy DW - Blood (2008)

Bottom Line: Acute inflammation is traditionally described as the influx of polymorphonuclear leukocytes (PMNs) followed by monocyte-derived macrophages, leading to resolution.To redress this we show, using lymphocyte-deficient RAG1(-/-) mice, that peritoneal T/B lymphocytes control PMN trafficking by regulating cytokine synthesis.In conclusion, as lymphocyte repopulation is also evident in human peritonitis, we hereby describe a transition in T/B cells from acute inflammation to resolution, with a central role in modulating the severity of early onset and orchestrating responses to secondary infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine and Translational Therapeutics, William Harvey Research Institute, London, United Kingdom.

ABSTRACT
Acute inflammation is traditionally described as the influx of polymorphonuclear leukocytes (PMNs) followed by monocyte-derived macrophages, leading to resolution. This is a classic view, and despite subpopulations of lymphocytes possessing innate immune-regulatory properties, seldom is their role in acute inflammation and its resolution discussed. To redress this we show, using lymphocyte-deficient RAG1(-/-) mice, that peritoneal T/B lymphocytes control PMN trafficking by regulating cytokine synthesis. Once inflammation ensues in normal mice, lymphocytes disappear in response to DP1 receptor activation by prostaglandin D(2). However, upon resolution, lymphocytes repopulate the cavity comprising B1, natural killer (NK), gamma/delta T, CD4(+)/CD25(+), and B2 cells. Repopulating lymphocytes are dispensable for resolution, as inflammation in RAG1(-/-) and wild-type mice resolve uniformly. However, repopulating lymphocytes are critical for modulating responses to superinfection. Thus, in chronic granulomatous disease using gp91phox(-/-) mice, not only is resolution delayed compared with wild-type, but there is a failure of lymphocyte re-appearance predisposing to exaggerated immune responses upon secondary challenge that is rescued by resolution-phase lymphocytes. In conclusion, as lymphocyte repopulation is also evident in human peritonitis, we hereby describe a transition in T/B cells from acute inflammation to resolution, with a central role in modulating the severity of early onset and orchestrating responses to secondary infection.

Show MeSH

Related in: MedlinePlus

Absence of repopulating lymphocytes during nonresolving inflammation. (A) Zymosan was injected into the peritoneal cavity of pg91phox knockout mice, which, when compared with controls, showed a more aggressive inflammatory response that failed to resolve. (B) FACS analysis of cell types present during resolution revealed a progressive repopulation of lymphocytes during resolution that was lower in pg91phox knockout mice. (C) Lymphocytes obtained from the resolution phase (72 hours) of normal strain-matched wild-type controls and comprising B1 cells, NK cells, and γ/δ T cells, as well as CD4+/CD25+ cells, were transferred back into the peritoneal cavity of gp91phox knockout mice (72 hours) and subsequently challenged, intraperitoneally, with LPS. Inflammation was reduced in gp91phox knockout mice that received resolution-phase lymphocytes compared with gp91phox mice alone. *P ≤ .05; **P ≤ .01 as determined by ANOVA, followed by Bonferroni t test, with data expressed as means plus or minus SEM.
© Copyright Policy - creativecommons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2602590&req=5

Figure 4: Absence of repopulating lymphocytes during nonresolving inflammation. (A) Zymosan was injected into the peritoneal cavity of pg91phox knockout mice, which, when compared with controls, showed a more aggressive inflammatory response that failed to resolve. (B) FACS analysis of cell types present during resolution revealed a progressive repopulation of lymphocytes during resolution that was lower in pg91phox knockout mice. (C) Lymphocytes obtained from the resolution phase (72 hours) of normal strain-matched wild-type controls and comprising B1 cells, NK cells, and γ/δ T cells, as well as CD4+/CD25+ cells, were transferred back into the peritoneal cavity of gp91phox knockout mice (72 hours) and subsequently challenged, intraperitoneally, with LPS. Inflammation was reduced in gp91phox knockout mice that received resolution-phase lymphocytes compared with gp91phox mice alone. *P ≤ .05; **P ≤ .01 as determined by ANOVA, followed by Bonferroni t test, with data expressed as means plus or minus SEM.

Mentions: Finally, the relevance of these findings to human inflammatory diseases was determined by examining the role of lymphocytes in gp91phox knockout mice, an experimental model of human chronic granulomatous disease caused by defects in the phagocyte respiratory burst oxidase, which generates microbicidal superoxide.24,25 Hence, patients with chronic granulomatous disease lack antimicrobial capacity and the ability to combat bacterial and fungal infections. Moreover, there is the associated occurrence of inflammatory granulomas in lung, liver, and skin, which in some instances may arise from sterile stimuli, suggesting that their formation may be due to incomplete degradation of inflammatory debris and/or impaired resolution of inflammation.26,27 gp91phox knockout mice were injected intraperitoneally with sterile zymosan and found to have elevated leukocyte numbers compared with controls, with inflammation failing to resolve (Figure 4A). See also Figure S8 for comparison of cell types in both animals at resolution. Fewer lymphocytes were found at 48 to 96 hours in gp91phox knockout mice, the time frame of resolution and lymphocyte repopulation in wild-type mice (Figure 4B). Lymphocytes obtained from the resolution phase (72 hours) of normal strain-matched wild-type controls which were therefore composed of B1, NK, and γ/δ T cells as well as CD4+/CD25+ cells, were transferred back to gp91phox knockout mice (72 hours) and challenged with LPS. Inflammation was reduced in knockout mice that received resolution-phase lymphocytes compared with gp91phox mice alone (Figure 4C). These results suggest that during ongoing, nonresolving inflammation, the absence of lymphocytes may account for susceptibility to superinfection and the associated hyperinflammatory response.


Novel biphasic role for lymphocytes revealed during resolving inflammation.

Rajakariar R, Lawrence T, Bystrom J, Hilliard M, Colville-Nash P, Bellingan G, Fitzgerald D, Yaqoob MM, Gilroy DW - Blood (2008)

Absence of repopulating lymphocytes during nonresolving inflammation. (A) Zymosan was injected into the peritoneal cavity of pg91phox knockout mice, which, when compared with controls, showed a more aggressive inflammatory response that failed to resolve. (B) FACS analysis of cell types present during resolution revealed a progressive repopulation of lymphocytes during resolution that was lower in pg91phox knockout mice. (C) Lymphocytes obtained from the resolution phase (72 hours) of normal strain-matched wild-type controls and comprising B1 cells, NK cells, and γ/δ T cells, as well as CD4+/CD25+ cells, were transferred back into the peritoneal cavity of gp91phox knockout mice (72 hours) and subsequently challenged, intraperitoneally, with LPS. Inflammation was reduced in gp91phox knockout mice that received resolution-phase lymphocytes compared with gp91phox mice alone. *P ≤ .05; **P ≤ .01 as determined by ANOVA, followed by Bonferroni t test, with data expressed as means plus or minus SEM.
© Copyright Policy - creativecommons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2602590&req=5

Figure 4: Absence of repopulating lymphocytes during nonresolving inflammation. (A) Zymosan was injected into the peritoneal cavity of pg91phox knockout mice, which, when compared with controls, showed a more aggressive inflammatory response that failed to resolve. (B) FACS analysis of cell types present during resolution revealed a progressive repopulation of lymphocytes during resolution that was lower in pg91phox knockout mice. (C) Lymphocytes obtained from the resolution phase (72 hours) of normal strain-matched wild-type controls and comprising B1 cells, NK cells, and γ/δ T cells, as well as CD4+/CD25+ cells, were transferred back into the peritoneal cavity of gp91phox knockout mice (72 hours) and subsequently challenged, intraperitoneally, with LPS. Inflammation was reduced in gp91phox knockout mice that received resolution-phase lymphocytes compared with gp91phox mice alone. *P ≤ .05; **P ≤ .01 as determined by ANOVA, followed by Bonferroni t test, with data expressed as means plus or minus SEM.
Mentions: Finally, the relevance of these findings to human inflammatory diseases was determined by examining the role of lymphocytes in gp91phox knockout mice, an experimental model of human chronic granulomatous disease caused by defects in the phagocyte respiratory burst oxidase, which generates microbicidal superoxide.24,25 Hence, patients with chronic granulomatous disease lack antimicrobial capacity and the ability to combat bacterial and fungal infections. Moreover, there is the associated occurrence of inflammatory granulomas in lung, liver, and skin, which in some instances may arise from sterile stimuli, suggesting that their formation may be due to incomplete degradation of inflammatory debris and/or impaired resolution of inflammation.26,27 gp91phox knockout mice were injected intraperitoneally with sterile zymosan and found to have elevated leukocyte numbers compared with controls, with inflammation failing to resolve (Figure 4A). See also Figure S8 for comparison of cell types in both animals at resolution. Fewer lymphocytes were found at 48 to 96 hours in gp91phox knockout mice, the time frame of resolution and lymphocyte repopulation in wild-type mice (Figure 4B). Lymphocytes obtained from the resolution phase (72 hours) of normal strain-matched wild-type controls which were therefore composed of B1, NK, and γ/δ T cells as well as CD4+/CD25+ cells, were transferred back to gp91phox knockout mice (72 hours) and challenged with LPS. Inflammation was reduced in knockout mice that received resolution-phase lymphocytes compared with gp91phox mice alone (Figure 4C). These results suggest that during ongoing, nonresolving inflammation, the absence of lymphocytes may account for susceptibility to superinfection and the associated hyperinflammatory response.

Bottom Line: Acute inflammation is traditionally described as the influx of polymorphonuclear leukocytes (PMNs) followed by monocyte-derived macrophages, leading to resolution.To redress this we show, using lymphocyte-deficient RAG1(-/-) mice, that peritoneal T/B lymphocytes control PMN trafficking by regulating cytokine synthesis.In conclusion, as lymphocyte repopulation is also evident in human peritonitis, we hereby describe a transition in T/B cells from acute inflammation to resolution, with a central role in modulating the severity of early onset and orchestrating responses to secondary infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine and Translational Therapeutics, William Harvey Research Institute, London, United Kingdom.

ABSTRACT
Acute inflammation is traditionally described as the influx of polymorphonuclear leukocytes (PMNs) followed by monocyte-derived macrophages, leading to resolution. This is a classic view, and despite subpopulations of lymphocytes possessing innate immune-regulatory properties, seldom is their role in acute inflammation and its resolution discussed. To redress this we show, using lymphocyte-deficient RAG1(-/-) mice, that peritoneal T/B lymphocytes control PMN trafficking by regulating cytokine synthesis. Once inflammation ensues in normal mice, lymphocytes disappear in response to DP1 receptor activation by prostaglandin D(2). However, upon resolution, lymphocytes repopulate the cavity comprising B1, natural killer (NK), gamma/delta T, CD4(+)/CD25(+), and B2 cells. Repopulating lymphocytes are dispensable for resolution, as inflammation in RAG1(-/-) and wild-type mice resolve uniformly. However, repopulating lymphocytes are critical for modulating responses to superinfection. Thus, in chronic granulomatous disease using gp91phox(-/-) mice, not only is resolution delayed compared with wild-type, but there is a failure of lymphocyte re-appearance predisposing to exaggerated immune responses upon secondary challenge that is rescued by resolution-phase lymphocytes. In conclusion, as lymphocyte repopulation is also evident in human peritonitis, we hereby describe a transition in T/B cells from acute inflammation to resolution, with a central role in modulating the severity of early onset and orchestrating responses to secondary infection.

Show MeSH
Related in: MedlinePlus