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3 and Membrane Lymphotoxin-1ß2 in Lymphotoxin-Induced Inflammation: Critical Role of TNF Receptor 1 Signaling1
*
Department of Epidemiology and Public Health and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; and
Department of Nervous System Diseases PRPN, F. Hoffmann-La Roche, Basel, Switzerland
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, TNFß) is a member of the immediate TNF
family that also includes TNF- and lymphotoxin-ß (LTß). LT is
produced by activated lymphocytes and functions as either a secreted
homotrimer or a membrane-associated heterotrimer that includes the
transmembrane protein LTß. Secreted LT3 can bind
to two cell surface receptors, TNFR1 and TNFR2, while the
membrane-bound heterotrimer LT1ß2 has been
shown to interact with a distinct receptor, LTßR. LT induces
inflammation at the sites of expression of a rat insulin
promoter-driven lymphotoxin (RIPLT) transgene in the pancreas and
kidney. To determine the role of the various ligands and their
receptors in LT-induced inflammation, mice deficient in either TNFR1,
TNFR2, or LTß were crossed to RIPLT-transgenic mice. Our results
indicate that LT-induced inflammation is dependent on the
interaction of LT3 with TNFR1, and there is no obvious
role for TNFR2, since in its absence, LT-induced inflammation is
quantitatively and qualitatively similar to that seen in the wild type.
However, the absence of LTß results in accentuated infiltration of
the kidney with an increase in the proportion of memory cells in the
infiltrate. These data show a crucial role for the secreted
LT3 signaling via TNFR1 in LT-induced inflammation,
and a separate and distinct role for the membrane
LT1ß2 form in this inflammatory process. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(LT, LT, TNFß)3 is
a member of
the immediate TNF family that includes TNF- and lymphotoxin-ß
(LTß). The LT homotrimer binds to two cell surface receptors, p55
(TNFR1) and p75 (TNFR2), which are members of the larger tumor necrosis
factor/nerve growth factor receptor family (1). LT also forms a
membrane-associated heterotrimer with a second subunit LTß (2). The
LT1ß2 complex binds to a distinct but
related receptor, the LTß receptor (LTßR) (3, 4).
LT has varied biologic activities, including a crucial role in
lymphoid organ development as demonstrated by analysis of mice that are
deficient in LT expression. These mice have no peripheral or
mesenteric lymph nodes (LN), no Peyer’s patches, and disorganized
splenic architecture (5, 6). This role of LT in lymphoid organ
development appears to be mediated in part via its interaction with the
LTß molecule, since recently we have shown that LTß-deficient
animals have no peripheral LN, a disrupted spleen, and no Peyer’s
patches; however, they do have mesenteric and cervical LN (7).
A role for LT in chronic inflammation has been suggested by its
ability to induce expression of ICAM-1 and VCAM-1 on endothelial cells
in vitro (8, 9). Studies with T cell clones indicate LT’s
importance (with TNF-) in the transfer of experimental allergic
encephalomyelitis. This effect on experimental allergic
encephalomyelitis is due in part to the up-regulation of VCAM-1 in the
central nervous system (10). In addition, LT induces inflammation at
the sites of targeted expression in transgenic animals. Mice transgenic
for LT under the control of the rat insulin promoter (RIPLT mice)
express the transgene in the pancreatic islets of Langerhans, proximal
convoluted tubules in the kidney and in the skin (11). The expression
of LT results in an infiltrate consisting of T cells, B cells,
macrophages, follicular dendritic cells, and interdigitating dendritic
cells at the sites of cytokine expression (12). A similar inflammatory
process is seen in RIPTNF- mice (13). RIPLT mice do not
spontaneously develop tissue damage, though in conjunction with
coexpression in the islets of the costimulatory molecule B7-1, the
animals do develop diabetes (J. Schwartz, R. Sacca, A. Kratz, and N.H.
Ruddle, manuscript in preparation). We have recently shown that
LT-induced chronic inflammation in RIPLT mice results in the formation
of an infiltrate that exhibits characteristics of lymphoid organs with
regard to cellular composition, compartmentalization, specialized
vascular system with vessels similar to high endothelial venules,
increased expression of markers associated with LN endothelium such as
mucosal addressin cell adhesion molecule (MAdCAM) and peripheral node
addressin (PNAd), and the ability to respond to Ag. These data suggest
that chronic inflammation has many of the characteristics of lymphoid
organ neogenesis, and that LT plays a crucial role in both
processes (12).
It is not clear as to which receptors mediate LT’s effects in
inflammation. This could occur via its interaction with p55TNFR1,
p75TNFR2, or the LTß receptor. Recent studies have shown that the
LT1ß2 heterotrimer is inefficient in
stimulating proinflammatory responses (14), suggesting that the LTßR
is less likely to be involved and that either p55TNFR1 and/or p75TNFR2
could play a significant role in LT-induced inflammation.
In the present study we addressed the function of the TNF receptors in
LT-mediated chronic inflammation by examining
LT-transgene-induced inflammation in p55TNFR1-/-,
p75TNFR2-/-, and LTß -/- mice. The
data presented here show that p55TNFR1 is essential for mediating
LT-induced inflammation, and in the absence of this receptor no
inflammation is observed. The lack of p75TNFR2 had no effect on LT
transgene-induced inflammation, which is quantitatively and
qualitatively similar to what is observed in the RIPLT wild-type
animals. Loss of LTß results in accentuated infiltration of the
kidney with an increase in the proportion of memory cells in the
infiltrate. These data suggest a crucial role for p55TNFR1 in
LT-induced inflammation and separate roles of LT3 and
LT1ß2 in this process.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The generation of RIPLT mice has been previously described (11). p75TNFR2-deficient mice were obtained from Mark Moore (Genentech, San Francisco, CA). p55TNFR1-deficient mice were obtained from Colin Stewart (Roche, Nutley, NJ). RIPLT mice were crossed to TNFR-deficient or LTß-deficient mice (7), then backcrossed to obtain RIPLT.p55TNFR1-/-, RIPLT.p75TNFR2-/-, and RIPLT.LTß-/- animals. Progeny were screened by Southern blot to determine the presence of the RIPLT transgene (11). The genotype with regard to TNFR1 and TNFR2 was assessed by PCR using primers specific for TNFR1 and TNFR2 as previously reported (15, 16). The presence of LTß was assessed by PCR analysis using the following primers to distinguish between the homozygous, heterozygous, and knockout animals: 5'GAGACAGTCACACCTGTTG, 5'CTTGTTCAATGGCCGATCC, and 5'CCTGTAGTCCACCACCATGTCG. The wild-type product is 120 bp while the homozygous knockout is 330 bp, and both 120 bp and 330 bp are seen in the heterozygous mice. All mice were maintained in a specific pathogen-free facility and evaluated between 6 and 12 wk of age.
Histology
Tissues were fixed in neutral buffered zinc-formalin, embedded in paraffin, sectioned at 5-µm thickness, and stained with hematoxylin and eosin following standard techniques.
Quantitation of pancreatic islet inflammation
For each mouse the number of inflamed vs normal islets present at three different levels in the pancreas was quantitated. The values shown represent averages from >10 mice in each group. Data were analyzed with Student’s t test. A p value of less than 0.05 was considered significant.
Cell isolation and FACS analysis
Cells were isolated from LN and kidneys by gentle pressure between microscope slides and washed three times with Hanks’ medium. Mononuclear cells were purified from the kidney preparations by centrifugation over Ficoll-Hypaque 1090, and resuspended in FACS buffer (5% goat serum, 5% heat-aggregated rabbit serum, 10 mM sodium azide in PBS). All Abs were obtained from PharMingen (San Diego, CA). For identification of memory and naive cells, 1 x 106 cells were incubated with 0.5 µg of anti-L-selectin for 30 min followed by incubation with phycoerythrin-conjugated anti-rat Ab for 30 min (1 µg). Cells were then incubated with FITC-conjugated CD4 (1 µg) for 30 min followed by incubation with biotinylated anti-CD44 (0.5 µg) Ab and streptavidin-cychrome (0.06 µg). In these samples, nonspecific binding of cychrome was blocked by addition of Fc block (1 µg). lymphocyte Peyer’s patch adhesion molecule (LPAM) expression was detected using 0.5 µg LPAM/106 cells followed by incubation with PE-conjugated anti-rat Ab. To determine the activation state of the T lymphocytes, phycoerythrin-conjugated CD69 (1 µg) was incubated with 1 x 106 cells. Samples were analyzed with a FACScan flow cytometer (Becton Dickinson, Mountain View, CA) with Cellquest software. Each experiment was repeated several times, and a minimum of three animals were examined in each group.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice were generated in which the RIPLT transgene was expressed in
the absence of either p55TNFR1 or p75TNFR2. To assess the role of these
receptors in transducing the LT signal that results in pancreatic
and kidney inflammation, sections of the pancreas and kidney were
evaluated histologically. In the RIPLT wild-type mice, a perivascular
infiltrate was observed as previously reported (Fig. 1
) (11). A similar infiltrate was seen in
mice that lacked the p75TNFR2 receptor (Fig. 1). However, mice that
lacked the p55TNFR1 receptor showed no evidence of inflammation in the
pancreas or the kidney (Fig. 1). These observations were quantitated by
comparing the number of inflamed islets with the total number of
islets. The values shown represent the average of all the mice in a
group (n = 10). As shown in Figure 2, there is no significant difference
between the number of inflamed islets observed in the p75TNFR2
heterozygous or knockout animals and the wild-type RIPLT animals.
However, there was a striking reduction in the number of inflamed
islets in animals that were heterozygous for the p55TNFR1 receptor
(p < 0.001), and there was a complete absence
of inflammation in the mice that expressed the RIPLT transgene but were
p55TNFR1 deficient. The same phenomenon was observed in the kidney,
where animals heterozygous for the p55TNFR1 receptor showed minimal
inflammation (data not shown), whereas the
RIPLT.p55TNFR1-/- mice had no kidney inflammation
(Fig. 1).
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To determine whether the inflammation observed in RIPLT mice is
solely the result of the secreted LT homotrimer
(LT3) acting through the p55TNFR1 receptor, or
whether the membrane LT1ß2 heterotrimer
plays a role in this inflammatory process via the LTß receptor,
RIPLT.LTß-/- mice were generated by crossing
LTß-/- mice with RIPLT mice. As shown in Figure 3A,
RIPLT.LTß-/- mice had pancreatic and kidney
inflammation similar to that of wild-type RIPLT mice. In fact, on
average there was an increase in the size of the inflammatory foci in
the interior portions of the RIPLT.LTß-/- kidney
compared with the RIPLT wild-type mice kidney (Fig. 3A). However, as shown in Figure 3B, there
was no difference between the number of inflamed islets in the pancreas
of the control vs RIPLT.LTß-/- animals.
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Though the RIPLT.p75TNFR2-/- and
RIPLT.LTß-/- animals showed histologically comparable
levels of inflammation, it was possible that there were qualitative
differences in the composition of the infiltrating cells. The cellular
composition of the kidney infiltrate was analyzed in these various
knockout animals and compared with the infiltrate of RIPLT wild-type
kidney as well as with lymphocytes from peripheral LN. A representative
experiment shows that the infiltrate of the RIPLT wild-type kidney
consists primarily of B and T cells with approximately three times more
B (58%) than T (23%) cells (see Figure 4) (12). This is in contrast to the
composition of LN, in which B cells (26%) are outnumbered by T cells
(67%) by approximately 3:1 (Fig. 4). In the infiltrate of both
RIPLT.p75TNFR2-/- and RIPLT.LTß-/-
animals, the proportions of B cells and T cells were similar to those
observed in the RIPLT wild-type kidneys (Fig. 4). These data suggest
that these molecules are not involved in determining the T and B cell
composition of the infiltrate.
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To determine whether the infiltrating T cells were of the memory
phenotype that predominate inflammatory foci or the naive phenotype
found mostly in lymphoid tissue, FACS analysis was conducted using CD44
and L-selectin as markers of cell maturity. The cells in the infiltrate
of the RIPLT wild-type kidney included both L-selectin high, CD44 low
(naive), and L-selectin low CD44 high (memory) cells. However, memory
cells outnumbered naive cells 4:1 (Fig. 5) compared with LN, which contained
<10% memory cells. The kidney infiltrate of
RIPLT.p75TNFR2-/- animals was similar to RIPLT
wild-type kidneys, with a comparable level of memory and naive cells
(3:1), whereas that of RIPLT.LTß-/- animals contained a
higher proportion of memory cells (12:1). The ratio of memory to naive
cells in the mesenteric LN of LTß-/- animals was within
the normal range observed in wild-type mesenteric LN. Therefore, the
increased number of memory cells in the RIPLT.LTß-/-
kidney infiltrate is not a reflection of the absence of peripheral LN.
To further characterize the infiltrate, the activation state of the
cells was determined by examining CD69 expression. As shown in Figure 6A, the majority of the cells
in the RIPLT wild-type kidney infiltrate did not express CD69, while
approximately 40% of the cells expressed CD69 at low levels. This is
comparable to the level of CD69 expression in LN cells as well as to
levels expressed by the cells in the RIPLT.p75TNFR2-/-
and RIPLT.LTß-/- kidney infiltrates.
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Since the majority of the infiltrating cells in the RIPLT kidney
did not express L-selectin, we hypothesized that they must be migrating
to the inflammatory sites through a mechanism independent of
L-selectin/PNAd interactions. We have previously demonstrated that the
endothelium of the RIPLT kidney expresses MAdCAM (12); we therefore
examined whether the infiltrating cells express its ligand, LPAM
(4ß7). Our studies show that approximately 50% of the cells in
the infiltrate of RIPLT kidneys expressed LPAM and that this percentage
of positive cells was comparable to the number observed in the
lymphocytes of LN as well as the infiltrate of
RIPLT.p75TNFR2-/- and RIPLT.LTß-/-
kidneys (Fig. 6
B). These results indicate that
LPAM/MAdCAM interactions may contribute to the accumulation of cells in
the RIPLT-inflamed kidneys.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study we examine the role of the TNF receptors, and the LTßR
in LT-induced inflammation by expressing the RIPLT transgene in mice
that are deficient in p55TNFR1, p75TNFR2, or LTß. In this manner we
show that p55TNFR1 plays a crucial role in LT-induced inflammation
as observed by the lack of inflammation in
RIPLT.p55TNFR1-/- mice and a dramatic decrease in
inflammation even in mice that are heterozygous for TNFR1
(RIPLT.p55TNFR1+/-). The absence of either p75TNFR2 or
LTß did not affect the ability of the transgene to induce
inflammation. Therefore we suggest that LT3, acting
through the p55TNFR1, is solely responsible for mediating this effect.
In mice lacking LTß we did observe that inflammation in the kidney
was accentuated, suggesting the possibility that in the absence of
LTß more LT3 is available to interact with p55TNFR1
and results in a more severe phenotype.
Similar to our results, other studies have shown a role for p55TNFR1 in
inflammation. In vitro studies using either TNF- mutants with
selective capacity to bind p55TNFR1 and p75TNFR2, or cultured
fibroblasts from p55TNFR1-deficient mice have shown that p55TNFR1 is
essential for adhesion molecule up-regulation and is therefore
implicated in the mechanisms of the proinflammatory response (22, 23).
In addition, these studies have implicated p75TNFR2 as having a role in
potentiating the induction of adhesion molecules by p55TNFR1. In animal
models, p55TNFR1 has been shown to be important in TNF--induced
expression of VCAM-1, E-selectin, and leukocyte organ infiltration (24)
and to have a role in initiating the proinflammatory effects that lead
to collagen-induced arthritis (15).
Our studies extend the finding that p55TNFR1 is the primary receptor
that mediates TNF-induced inflammation to include it as the primary
receptor involved in LT-induced inflammation. In addition, in
contrast to other studies, we observe no potentiating effects of
p75TNFR2, since in mice that express the RIPLT transgene but lack
p75TNFR2 the extent and nature of the inflammation is not altered.
Other investigators have proposed that p75TNFR2 mediates TNF signals
when it recognizes TNF in its membrane-bound form (25). The
LT3 homotrimer is secreted, the membrane-bound
heterotrimer LT1ß2 binds to a distinct
LTßR, while a minor form of the heterotrimer,
LT2ß1, has been shown to interact with
p55TNFR1 (26). Therefore, the membrane form of LT does not use
p75TNFR2 in its signaling. The p75TNFR2 receptor has also been
suggested to participate in TNF/LT signaling by capturing and
"passing" the ligand to the p55TNFR1 (27), thus enhancing the
effect when ligand concentration is limiting. We do not observe these
effects in our model, as we do not see any diminution of inflammation
in the absence of p75TNFR2. However, the high concentrations of LT
produced by the transgene may not be limiting and thus may eliminate a
necessity for a "concentrating effect" mediated through p75TNFR2
ligand passing.
We have shown that in the absence of LTß, the RIPLT-induced
inflammation is qualitatively altered. Furthermore, the extent of the
inflammation in the kidney was accentuated. In RIPLT wild-type animals
the inflammatory foci were observed primarily around the outer regions
of the kidney, whereas in RIPLT.LTß-/- mice there was
an increase in the size of the foci in the interior portions of the
kidney. The qualitative difference with regard to T cell phenotype
observed in RIPLT.LTß-/- mice reinforces the concept
that the LT1ß2 complex has a principal
role in lymphoid organ development and a secondary function in the
inflammatory process, which could include its perpetuation.
We have previously shown (12) that the chronic inflammatory lesions
that develop in the kidney and pancreas at the sites of transgene
expression resemble lymphoid tissue with regard to cellular
composition, delineated B and T cell areas, primary and secondary
follicles, and a vasculature that is lined with high endothelial
venules that are usually found in LN. Furthermore, these high
endothelial venules express adhesion molecules (PNAd and MAdCAM)
normally expressed in LN. In addition, the infiltrates respond to Ag
and undergo Ig class switching when the mice are immunized. This
organization of LT-induced inflammation together with our finding
that mice deficient in LT completely lack LN (5, 6) suggest that
LT is critical for the development and organization of lymphoid
tissue. Recently we have determined that the development of peripheral
LN is mediated through association of LT with LTß signaling
through the LTßR (7). LTß plays no apparent role in the development
of mesenteric and cervical LN, as these develop normally in
LTß-deficient mice (7).
The recruitment of lymphocytes to RIPLT-inflamed tissue probably occurs
through multiple adhesion molecule interactions including
PNAd/L-selectin, ICAM/LFA-1, VCAM-1/VLA-4, and MAdCAM/LPAM. One
difference between the peripheral and mesenteric LN is that the former
express PNAd while the latter do not. PNAd mediates the trafficking of
L-selectin-positive cells (naive) to the peripheral LN, while MAdCAM is
involved in the recruitment of cells to the mesenteric LN (28). In the
RIPLT.LTß-/- mice, the phenotype of the infiltrating
cells is skewed toward a more memory phenotype (L-selectin low, CD44
high), having about two to three times more memory cells than are found
in the RIPLT wild type. It is possible that PNAd expression on the
endothelial cells of the vasculature is diminished in the
RIPLT.LTß-/- mice, thus affecting the recruitment of
naive cells. Studies are currently in progress to determine the ability
of LT1ß2 to induce PNAd in vivo and in
vitro. It is also possible that there is an alteration in chemokine
production in the absence of LTß. If this were the case it could
influence the ratio of memory to naive cells in the kidney infiltrate
of RIPLT.LTß-/-.
In conclusion, our studies are the first to show that LT induces its
inflammatory effects via the LT3 homotrimer interaction
with TNFR1 and strengthens the concept that LT alone has activities
that are independent of LTß. We further show that the
LT1ß2 heterotrimer may influence the
phenotype of the infiltrate observed in the inflammatory response,
suggesting that the secreted and membrane-bound forms of LT have
distinct and separable activities in the inflammatory process.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Nancy H. Ruddle, Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College Street, P.O. Box 208034, New Haven, CT 06520-8034. E-mail address:
3 Abbreviations used in this paper: LT, lymphotoxin-; LTß, lymphotoxin-ß; p55TNFR1, p55 TNF receptor-1; p75TNFR2, p75 TNF receptor-2; LN, lymph nodes; LTßR, lymphotoxin-ß receptor; RIPLT, rat insulin promoter-driven lymphotoxin; MAdCAM, mucosal addressin cell adhesion molecule; LPAM; lymphocyte Peyer’s patch adhesion molecule; PNAd, peripheral node addressin.
Received for publication July 2, 1997. Accepted for publication September 23, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß revealed in lymphotoxin ß-deficient mice. Immunity 6:491.[Medline]
production in islets leads to insulitis, not diabetes: distinct patterns of inflammation in TNF- and TNF-ß transgenic mice. J. Immunol. 149:4136.
cytotoxic and proinflammatory activities by p55-receptor- and p75 receptor-selective TNF- mutants. EMBO J. 13:843.[Medline]
activation. J. Immunol. 153:5274.[Abstract]
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I. Gramaglia, D. N. Mauri, K. T. Miner, C. F. Ware, and M. Croft Lymphotoxin {alpha}{beta} Is Expressed on Recently Activated Naive and Th1-Like CD4 Cells but Is Down-Regulated by IL-4 During Th2 Differentiation J. Immunol., February 1, 1999; 162(3): 1333 - 1338. [Abstract] [Full Text] [PDF]
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C. A. Cuff, J. Schwartz, C. M. Bergman, K. S. Russell, J. R. Bender, and N. H. Ruddle Lymphotoxin {alpha}3 Induces Chemokines and Adhesion Molecules: Insight into the Role of LT{alpha} in Inflammation and Lymphoid Organ Development J. Immunol., December 15, 1998; 161(12): 6853 - 6860. [Abstract] [Full Text] [PDF]
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P. A. Koni and R. A. Flavell A Role for Tumor Necrosis Factor Receptor Type 1 in Gut-associated Lymphoid Tissue Development: Genetic Evidence of Synergism with Lymphotoxin {beta} J. Exp. Med., June 15, 1998; 187(12): 1977 - 1983. [Abstract] [Full Text] [PDF]
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