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Cutting Edge: Critical Role for Mesothelial Cells in Necrosis-Induced Inflammation through the Recognition of IL-1 Released from Dying Cells¹

Tatjana Eigenbrod^*, Jong-Hwan Park^*, Jürgen Harder^*, Yoichiro Iwakura and Gabriel Núñez^2,*

^* Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109; and Center for Medical Science, Institute of Medical Science, University of Tokyo, Tokyo, Japan

	Abstract

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Endogenous danger signals released from necrotic cells are thought to be sensed by phagocytes leading to secretion of IL-1 and neutrophilic recruitment. However, the mechanisms for IL-1 production and IL-1-mediated sterile inflammation remain poorly understood. We report here that necrotic cell extracts elicited little secretion of CXCL1 and IL-6 from macrophages but robust production in mesothelial cells. The induction of CXCL1 as well as activation of NF-B and MAPKs by cytosolic extracts required the presence of IL-1 in the necrotic cell. Conversely, expression of IL-1R and MyD88 but not IL-1, RICK, TLR2, TLR4, TRIF, or inflammasome components in mesothelial cells was critical for the production of CXCL1. Furthermore, IL-1 was critical to induce the recruitment of neutrophils in the peritoneal cavity via CXCR2. These studies show that IL-1 is a key danger signal released from necrotic cells to trigger CXCL1 secretion and recruitment of neutrophils via IL-1R/MyD88 on neighboring mesothelial cells.

	Introduction

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Both cell injury and microbial infection stimulate potent inflammatory responses that are required for the removal of the damaged tissue and invading organisms, respectively. In infection, the induction of inflammatory responses relies on the activation of host pattern-recognition receptors including TLRs and Nod-like receptors that recognize conserved and unique microbial structures (1, 2). The mechanism that activates inflammation in response to cell injury is less understood. There is evidence that necrotic cells release endogenous molecules (also called danger signals) that provide adjuvant activity (3). Some of these intracellular danger signals, including HMGB1 (high-mobility group box 1 protein), uric acid, galectins, S100 proteins, thioredoxin, and possibly heat-shock proteins directly activate the innate immune system (3, 4). Although necrotic cells and several intracellular danger signals including HMGB1 and heat-shock proteins have been reported to stimulate TLR2 and TLR4 (5, 6, 7, 8), acute inflammation induced by necrotic cell extracts is largely independent of TLRs in vivo (9). Notably, neutrophilic infiltrate triggered by heat-killed cells or liver extracts was markedly reduced in mice deficient in MyD88 or IL-1R (9). Blockade studies with anti-IL-1 Ab revealed that IL-1, but not IL-1β, was critical to induce neutrophil recruitment in response to necrotic cells (9). It was postulated that necrotic cells release an unknown danger signal that stimulates phagocytic cells to secrete IL-1, but this hypothesis remains untested (9, 10). Furthermore, the mechanisms by which necrotic cells induce IL-1 to promote neutrophilic infiltrate and how IL-1 triggers neutrophil recruitment remain unknown. In this study, we provide evidence for a mechanism to explain how necrotic cells activate the IL-1R to induce the recruitment of neutrophils through the release of IL-1 from necrotic cells and induction of CXCL1 in mesothelial cells.

	Materials and Methods

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Mice

Myd88^–/–, Trif^–/–, Rick^–/–, Casp-1^–/–, Asc^–/–, Tlr2/4^–/–, Il-1a^–/–, and Cxcr2^–/– mice in a C57BL/6 background have been described (11, 12, 13) C57BL/6 mice were purchased from The Jackson Laboratory. All animal studies were approved by the University of Michigan Committee on Use and Care of Animals.

Preparation of necrotic cell extracts and liver homogenate

Bone marrow-derived macrophages were prepared as described (14). Bone marrow-derived dendritic cells (DCs)³ were differentiated in RPMI 1640 supplemented with 10% FCS, 0.1% 2-ME, and 20 ng/ml GM-CSF. Cells were suspended at 10⁸cells/ml and subjected to five freeze-thaw cycles. Cells were centrifuged and supernatant was collected. Mouse liver was manually homogenized in 1 ml of DMEM per gram of tissue. After five freeze-thaw cycles, the homogenate was centrifuged and supernatant was collected.

Cell isolation and stimulation with necrotic cell lysates

Mesothelial cells (MCs) were isolated as described (see Ref. 14 and supplemental methods).⁴ Peritoneal macrophages were harvested by peritoneal lavage four days after injection of 4% thioglycollate. Cells were stimulated in triplicate with necrotic macrophage supernatant (at 1/10 dilution) or liver homogenate (at 1/100 dilution) for 6 h. Stimulation with LPS, Pam3CSK, polyinosinic:polycytidylic acid, lipid A (all purchased from InvivoGen), or KF1B (provided by Dr. K. Fukase, Osaka University, Osaka, Japan) served as positive control. For blockade of IL-1R signaling, cells were prestimulated with rIL-1R antagonist at 500 ng/ml (Amgen) for 1.5 h and then stimulated with necrotic cell extracts or liver homogenate as above.

Immunoblotting and cytokine measurements

Membranes were probed with Abs against IB, phosphorylated IB, p38, phosphorylated p38, JNK, and phosphorylated JNK (Cell Signaling) as described (14). Levels of CXCL1 and IL-6 were measured by ELISA (R&D Systems).

IL-1-mediated neutrophil recruitment in vivo

Wild-type (WT) and Cxcr2^–/– mice received mouse rIL-1 (0.05 ng/g body weight, R&D) by i.p. injection and peritoneal lavage was performed 6 h later. Cells were counted, stained with PE-labeled anti-Gr-1 Ab (Pharmingen) or control PE-labeled Ab, and the percentage of Gr-1-positive cells was determined by flow cytometry. Analysis was verified by counting neutrophil granulocytes on stained cytospin slides. Mice were injected i.p. with extracts from 1.5 x 10⁷ necrotic DCs per mouse obtained from WT or Il-1a^–/– mice. Peritoneal lavage and cell analysis were performed as described above.

Statistical analysis

Statistical significance between groups was determined by two tailed Student’s t test. Differences were considered significant when p < 0.05.

	Results and Discussion

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MCs, but not macrophages, secrete CXCL1 and IL-6 in response to cytosolic extracts from necrotic macrophages or liver

Injection of necrotic cells or liver extracts in the peritoneal cavity of mice induce the recruitment of neutrophils, but the mechanism is unknown (9). To determine the cells that respond to necrotic cells, MCs that line the organs and body cavities and macrophages were stimulated with cytosolic extracts from necrotic macrophages or liver homogenate. Primary MCs secreted CXCL1, a chemokine that is a potent inducer of neutrophil recruitment (15), and IL-6 after incubation with necrotic cell or liver extracts (Fig. 1, A and B, and supplemental figure 1). In contrast, bone marrow-derived or peritoneal macrophages produced little or no CXCL1 or IL-6 in response to the same cell extracts, although they secreted robust levels of both proinflammatory molecules after LPS stimulation (Fig. 1, A, C, and D). These results indicate that MCs, but not macrophages, produce CXCL1 or IL-6 after stimulation with necrotic cell or liver extracts.

View larger version (17K): [in this window] [in a new window]   FIGURE 1. Necrotic cell extracts and liver homogenate induce CXCL1 and IL-6 in MCs but not in macrophages. A and B, Bone marrow-derived macrophages (BMDM) and MCs were stimulated with extracts from necrotic macrophages (M), liver homogenate (Liv), and LPS (100 ng/ml) or left untreated (–) for 6 h. C and D, Peritoneal macrophages were stimulated with the same extracts as in A and B or with LPS for 24 h. CXCL1 (A and C) and IL-6 (B and D) levels were measured in cell-free supernatants by ELISA. Values represent the mean of triplicate wells ± SD. Results are representative of at least three independent experiments.

We determined next the role of several innate immune receptors and adaptors in the secretion of CXCL1 by MCs. Secretion of CXCL1 induced by stimulation with the cytosolic contents of necrotic macrophages or liver homogenate was independent of RICK, an adaptor that is required for Nod1 and Nod2 signaling (Fig. 2A). Similarly, caspase-1 and Asc, an adaptor required for inflammasome activation (11, 16), were dispensable for CXCL1 secretion (Fig. 2B). Furthermore, MCs lacking TLR2/TLR4 did not respond to lipid A (TLR4 agonist) and Pam3CSK (TLR2 agonist) but produced comparable amounts of CXCL1 as WT cells in response to macrophage or liver cell extracts (Fig. 2C). Notably, CXCL1 secretion was abolished in MCs deficient in MyD88, an adaptor essential for TLR/IL-1R signaling, whereas TRIF, an adaptor also involved in TLR signaling, was dispensable (Fig. 2, D and E). These results indicate that MyD88 is critical for CXCL1 production by MCs in response to cytosolic extracts from necrotic macrophages or liver homogenate.

View larger version (30K): [in this window] [in a new window]   FIGURE 2. MyD88 is essential for the induction of CXCL1 secretion by necrotic cell extracts and liver homogenate. MCs from WT or mutant mice deficient in Rick (A), Casp-1 (caspase-1) or Asc (B), Tlr2/Tlr4 (C), Trif (D), Myd88/Trif or Myd88 (E) were stimulated with necrotic macrophage cell extracts (M) or liver homogenate (Liv) for 6 h. Stimulation with LPS, KF1B, lipid A, Pam3CSK, and polyinosinic:polycytidylic acid (Poly(I:C)) was used as control. Values represent the mean of triplicate wells ± SD. CXCL1 levels were measured in cell-free supernatants by ELISA. Results are representative of three independent experiments. **, p < 0.01 between WT and mutant MCs.

MyD88 is required for both TLR and IL-1R signaling (17). To assess the role of IL-1R in CXCL1 secretion, we first tested whether rIL-1 could induce the production of the chemokine in MCs. Stimulation of MCs with as little as 10 pg/ml IL-1 induced the secretion of detectable amounts of CXCL1 (Fig. 3A). Notably, the production of CXCL1 induced by cytosolic extracts from necrotic macrophages, liver tissue, or rIL-1 was blocked by an rIL-1R antagonist (Fig. 3B and supplemental figure 2), a molecule that inhibits IL-1R signaling (18). Similar results were obtained when necrosis was induced by other stimuli (supplemental figure 3). Furthermore, MCs lacking IL-1R produced little or no CXCL1 after stimulation with the cytosolic extracts when compared with MCs from wild-type mice (Fig. 3C). CXCL1 production is induced via NF-B and MAPK activation (19). To determine whether necrotic macrophages or liver homogenate induce NF-B and MAPK activation, MCs were stimulated with the cellular extracts and the MC lysates were immunoblotted with Abs that recognize activated forms of NF-B, JNK, and p38. Both cytosolic extracts induced rapid phosphorylation and degradation of I-B as well as phosphorylation of p38 and JNK in WT MCs (Fig. 3D). The activation of NF-B and MAPKs induced by cytosolic extracts from necrotic macrophages and liver homogenate was abolished or greatly impaired, respectively, in MCs lacking IL-1R (Fig. 3, D and E). The impairment in signaling of MCs deficient in IL-1R was specific in that the mutant cells responded normally to KF1B, a synthetic Nod1 agonist known to induce CXCL1 production in MCs (14). These results indicate that IL-1R is critical for CXCL1 production and signaling induced by cytosolic extracts from necrotic cells or liver homogenate in MCs.

View larger version (17K): [in this window] [in a new window]   FIGURE 3. Production of CXCL1 and induction of signaling cascades by necrotic cell extracts and liver homogenate require IL-1R. A, MCs were stimulated with the indicated amounts of rIL-1 for 6 h. B, MCs were stimulated with necrotic macrophage cell extracts (M), liver homogenate (Liv), or 1 ng/ml IL-1 for 6 h in the presence and absence of IL-1R antagonist (IL-1Ra; 500 ng/ml). CXCL1 levels were measured in cell-free supernatants by ELISA. Results are representative of three independent experiments. **, p < 0.01 between untreated and IL-1Ra-treated cultures. C, MCs from wild-type (WT) or IL-1R-deficient (Il-1r–/–) mice were stimulated with M, Liv, or rIL-1 as a control for 6 h. CXCL1 levels were measured in cell-free supernatants by ELISA. Values represent the mean of triplicate wells ± SD. Results are representative of three independent experiments. **, p < 0.01 between WT and mutant MCs. D and E, MCs from WT or Il-1r–/– mice were stimulated with M (D), Liv or KF1B (Nod1 agonist) (E) for the indicated times and the activation of NF-B and MAPKs was determined by immunoblotting with the indicated Abs. Results are representative of three independent experiments. p-, Phosphorylated.

The presence of IL-1 in necrotic macrophages or liver extracts, but not in MCs, is required for CXCL1 production

Next, we studied the requirement of IL-1 for CXCL1 production by MCs. Cytosolic extracts from necrotic macrophages or necrotic liver lysates derived from WT mice induced CXCL1, but those from cells deficient in IL-1 were greatly impaired in inducing the chemokine (Fig. 4A). Similar results were found after stimulation with necrotic extracts from WT or IL-1-deficient DCs (supplemental figure 4). In line with these results, the activation of NF-B and MAPKs induced by liver homogenate lacking IL-1 was greatly reduced (Fig. 4B). Notably, the deficiency in the induction of NF-B and MAPK activation observed in liver homogenate lacking IL-1 was comparable to that found when MCs deficient in IL-1R were stimulated with liver extracts from wild-type mice (compare Figs. 4B and 3B). Furthermore, production of CXCL1 triggered by the cytosolic contents of necrotic cells or liver homogenate in WT and IL-1-deficient MCs was similar (Fig. 4C). Thus, IL-1 is required in the necrotic cell but not in MCs to elicit CXCL1 secretion.

View larger version (26K): [in this window] [in a new window]   FIGURE 4. The presence of IL-1 in necrotic cell extracts is essential for induction of CXCL1 and signaling cascades in MCs. A, MCs were stimulated with necrotic macrophage cell extracts (M) or liver homogenate (Liv) from WT or IL-1-deficient mice (Il-1–/–) for 6 h. CXCL1 levels were measured in cell-free supernatants by ELISA. Results are representative of three independent experiments. **, p < 0.01 between cell extracts from WT and Il-1–/– mice. B, MCs were stimulated with necrotic Liv from WT or Il-1–/– mice for the indicated times. Activation of NF-B and MAPKs was determined by immunoblotting with indicated Abs. Results are representative of three independent experiments. p-, Phosphorylated. C, MCs from WT and Il-1–/– mice were stimulated with M or Liv from WT mice for 6 h and CXCL1 levels were measured in cell-free supernatants. D, Mice were injected i.p. with 1.5 x 107 DCs obtained from WT or Il-1–/– mice (n = 14 per group; data pooled from two independent experiments) or with saline (n = 7) and peritoneal lavage was performed after 6 h. **, p < 0.01 between groups receiving WT or Il-1–/– DCs, values ± SEM. E, Groups of WT and Cxcr2-deficient mice (Cxcr2–/–) (n = 7 per group) received rIL-1 i.p. (0.05 ng/g body weight) and peritoneal lavage was performed after 6 h. **, p < 0.01 between groups receiving WT or Il-1–/– DCs, values ± SEM.

Necrotic cells deficient in IL-1 exhibit an impaired ability to recruit neutrophils in vivo

To investigate the relevance of IL-1 released by necrotic cells in vivo, extracts from necrotic DCs obtained from WT or IL-1-deficient mice were injected i.p. into mice and neutrophil recruitment into the peritoneal cavity was evaluated. Mice injected with IL-1-deficient necrotic cell lysates showed a reduced recruitment of neutrophils as compared with mice treated with cell extracts from WT mice (Fig. 4D). Thus, IL-1 released by dying cells plays an essential role in neutrophil recruitment in vivo.

IL-1 elicits neutrophil recruitment via CXCR2

We showed in Fig. 3A that picogram amounts of IL-1 induce CXCL1 secretion in MCs. To determine whether the presence of IL-1 is sufficient to trigger neutrophil recruitment, we administered IL-1 to mice i. p. and the number of neutrophils present in the peritoneal cavity was determined by flow cytometry. At 6 h postinjection, IL-1 elicited the recruitment of neutrophils ( 3.5 x 10⁵/ml) (Fig. 4D and supplemental figure 5). This is in line with previous studies (20). Importantly, the recruitment of neutrophils triggered by IL-1 was greatly impaired in mice lacking CXCR2, the receptor for the chemokine CXCL1 (21). These results indicate that IL-1 is sufficient to elicit the recruitment of neutrophils and that this is mediated via CXCR2.

Previous studies suggested that dying cells release danger signals that stimulate innate immune cells to secrete IL-1, triggering the recruitment of neutrophils at sites of cellular injury (9). However, the mechanism of IL-1 production and how IL-1 induces neutrophil recruitment remained unknown. In the present studies, we provide evidence that IL-1, a biologically active molecule present in the cytosol of most cells and organs, including macrophages, keratinocytes, liver, spleen, lung and intestine (22, 23), is an important danger signal released from necrotic cells to elicit CXCL1 secretion by MCs and neutrophil recruitment via CXCR2 (supplemental figure 6). Our results suggest that phagocytic cells do not play a key role in the sensing of injured cells and induction of inflammation as previously proposed (9). Instead, we propose a model in which necrosis is recognized directly by MCs through the passive release of IL-1 from dying cells. The results do not rule out that endogenous molecules other than IL-1 also contribute to the detection of necrosis and induction of inflammation. The current study is focused on MCs, because the work was aimed at understanding the response of the peritoneal cavity to necrotic cells. However, IL-1 is known to induce the expression of CXCL1 in epithelial cells, fibroblasts, and MCs, and MCs are known to produce multiple chemokines and cytokines in response to IL-1 (24, 25, 26). Thus, the production of CXCL1 is likely to be mediated by a variety of cells in response to IL-1 released from dying cells. Our findings suggest that cell injury and microbial stimulation used similar mechanism and signaling pathways to elicit inflammation. In infection, molecules such as IL-1β are actively secreted by macrophages in response to microbial infection and activate the IL-1R. In sterile inflammation, IL-1 is passively released from dying cells leading to the activation of the IL-1R. Thus, both microbial and sterile cell injury share the same receptors to trigger acute inflammation in the host.

	Acknowledgments

 
We thank Richard Flavell, Shizuo Akira, and Millenium Pharmaceuticals for generous supply of mutant mice, Koichi Fukase and Amgen for reagents, Joel Whitfield for technical support, and Sherry Koonse for excellent animal husbandry.

	Disclosures

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The authors have no financial conflict of interest.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI063331 and AI064748 (to G.N.). T.E. was supported by a fellowship from the Jung-Stiftung für Wissenschaft und Forschung and by a fellowship from the German Research Foundation (Deutsche Forschungsgemeinschaft), and J. Harder was supported by a Heisenberg-Stipendium of the Deutsche Forschungsgemeinschaft.

² Address correspondence and reprint requests to Dr. Gabriel Núñez, Department of Pathology, University of Michigan Medical School, 4215 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109. E-mail address: bclx{at}umich.edu

³ Abbreviations used in this paper: DC, dendritic cell; MC, mesothelial cell; WT, wild type.

⁴ The online version of this article contains supplemental material.

Received for publication July 16, 2008. Accepted for publication October 22, 2008.

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