In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 1 ( 2012-01-03)
Abstract:
The results of our investigation identify a pathway for acute tissue inflammation that involves the NK cell–epithelial–neutrophil axis in which CD137–CD137L interactions play a critical role in the signaling process that induces inflammation ( Fig. P1 ). We have demonstrated one especially important finding: Reverse signaling through a member of the costimulatory ligand family (CD137L) propagates tissue inflammation in a disease context. This process may be implicated in various other types of acute tissue inflammation. Finally, we asked which CD137-expressing immune cells could induce TECs to trigger the CD137L signaling pathway leading to production of CXCL1 and CXCL2. The membrane that separates the TEC layer from other connective tissue cells was disrupted rapidly after renal IRI was induced, and natural killer (NK) cells approached TECs. Expression of CD137 was induced on infiltrating NK cells soon after the induction of renal IRI. Transferring normal, unmutated NK cells completely restored renal IRI in CD137-KO mice. In addition, activated NK cells that expressed CD137 on their cell surface stimulated TECs to produce high levels of functional CXCL1 and CXCL2. We further asked how CD137L signals mediate renal IRI. Other studies have demonstrated that deficiency of signaling-receptor molecules of the TLR family (namely, TLR2 and TLR4) in TECs results in severe defects in neutrophil infiltration in renal IRI ( 3 , 4 ), as seen in CD137-KO mice. To investigate whether CD137L signals in TECs are a prerequisite for renal IRI, we devised an experimental system in which signaling through CD137L in TECs is allowed in CD137L-KO mice. Implantation of normal, unmutated TECs in CD137L-KO mice restored renal IRI. Reduced production of signaling molecules of the chemokine family, namely CXC receptor ligand 1 (CXCL1) and CXC receptor ligand 2 (CXCL2), in TECs and the consequent impairment in recruitment of neutrophils were associated with the resistance to renal IRI in CD137 or CD137L-KO mice. In vitro stimulation of TECs by using fusion proteins rapidly induced the release of CXCL1 and CXCL2, in turn inducing migration of neutrophils in a CXC receptor 2 (CXCR2)-dependent manner. We began our studies by observing that the signaling receptor molecule CD137 ligand (CD137L) was constitutively (constantly) expressed on the surface of TECs and that mice with mutations preventing the expression of its receptor (CD137-KO mice) were severely impaired in renal IRI. We asked how interactions between the CD137 receptor and the molecule that it recognizes (CD137L) mediate renal IRI. Initial experiments indicated that CD137 expression on hematopoietic cells (cells capable of developing into many types of blood cells) were required for renal IRI. Stimulation using specific molecules that target CD137 blocked rather than enhanced renal IRI, suggesting that reverse signaling through CD137L played a pivotal role in renal IRI. Further supporting this explanation, engagement of CD137L (using a recombinant or modified protein that fuses the ligand) resulted in complete recovery from renal IRI in CD137-KO mice. In the disorder known as “renal ischemia-reperfusion injury” (IRI), hypoxic (low oxygen supply) cell injuries occur early during the ischemic (low blood flow) phase, followed by inflammatory responses in the reperfusion phase (when blood flow returns). These injured cells release various inducers of inflammation, including proinflammatory cytokines (specific immune molecules) and endogenous danger signals recognized by a type of receptors called “Toll-like receptors” (TLRs). In kidneys with reduced blood flow (ischemic kidneys), activation of TLR and two types of specific immune molecules (cytokines and complements) induces expression of multiple proinflammatory molecules known as “chemokines.” The tubular epithelium is a major site for cell injury and for such changes. Epithelial cells known as “tubular epithelial cells” (TECs) usually are damaged. Even though the arrival of neutrophils to these damaged cells is characteristic of acute inflammation, it is not known precisely how damaged TECs regulate penetration of neutrophils (neutrophil infiltration) into postischemic kidneys. Inflammation, an important immune process, is triggered by a variety of stress conditions ( 1 ). Because epithelial cells line the surfaces of organs and internal cavities, they are particularly vulnerable to injuries by pathogenic microorganisms, toxic factors, and physical trauma. The resulting epithelial damage causes myriad changes, including many changes important in inflammation ( 2 ). Although progress has been made in understanding how molecules called “antigens” on the surfaces of stressed epithelial cells regulate immune cells, little is known about receptor molecules that permit immune cells to target such stressed epithelial cells. Here, we describe cellular signaling in a pathway involving a particular epithelial cell and the recruitment of immune players known as “neutrophils.”
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1112256109
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2012
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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