Paired immunoglobulin-like receptor B (PIR-B) negatively regulates macrophage activation in experimental colitis.
OBJECTIVE
Innate and adaptive immune responses are regulated by cross talk between activation and inhibitory signals. Dysregulation of the inhibitory signal can lead to aberrant chronic inflammatory diseases such as the inflammatory bowel diseases (IBD). Little is known about negative regulation of innate intestinal immune activation. We examined the role of the inhibitory receptor paired immunoglobulin-like receptor B (PIR-B) in the regulation of macrophage function in innate intestinal immunity.


METHODS
We examined the susceptibility of Pirb-/- and wild-type (WT) mice to dextran sodium sulfate (DSS)-induced colitis. We assessed proinflammatory cytokine release and mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF-kappaB) activation in Pirb-/- and WT macrophages following Escherichia coli stimulation. Macrophage transfer experiments were performed to define the role of PIR-B in the negative regulation of macrophage function in DSS-induced colitis. We also assessed expression of PIR-B human homologues (immunoglobulin-like transcript [ILT]-2 and ILT-3) in colon biopsy samples from healthy individuals (controls) and patients with IBD.


RESULTS
Pirb-/- mice had increased susceptibility to DSS-induced colitis. In vitro analysis showed increased production of proinflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor alpha) and activation of MAPK and NF-kappaB in Pirb-/- macrophages following bacterial activation. Adoptive transfer of bone marrow-derived Pirb-/- macrophages into WT mice was sufficient to increase disease susceptibility. ILT-2 and ILT-3 were expressed on CD68+ and CD68- mononuclear cells and intestinal epithelium in colon biopsy samples from patients and controls.


CONCLUSIONS
PIR-B negatively regulates macrophage functions in response to pathogenic bacteria and chronic intestinal inflammatory responses. Inhibitory receptors such as PIR-B might be used as therapeutic targets for treatment of patients with IBD.
Munitz
Ariel
A
Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Cole
Eric T
ET
Beichler
Amanda
A
Groschwitz
Katherine
K
Ahrens
Richard
R
Steinbrecher
Kris
K
Willson
Tara
T
Han
Xiaonan
X
Denson
Lee
L
Rothenberg
Marc E
ME
Hogan
Simon P
SP
D000293:Adolescent; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D001706:Biopsy; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000472:pathogenicity; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000637:transplantation; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000032:analysis; D011971:Receptors, Immunologic / Q000032:analysis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D015703:Antigens, CD; D016207:Cytokines; D018836:Inflammation Mediators; C105299:LILRB1 protein, human; C107907:LILRB4 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C105949:Pirb protein, mouse; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D016264:Dextran Sulfate; D020928:Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse
FASEB J. 2004 Oct;18(13):1550-2
15289440
J Exp Med. 1999 Jan 18;189(2):309-18
9892613
J Exp Med. 2007 Oct 29;204(11):2719-31
17954568
Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15086-90
10611342
J Biol Chem. 1997 Mar 14;272(11):7320-7
9054430
Immunology. 2005 Aug;115(4):433-40
16011512
Nat Immunol. 2002 Jun;3(6):542-8
12021780
Cytometry A. 2003 Oct;55(2):61-70
14505311
Am J Pathol. 2002 Feb;160(2):425-31
11839562
J Clin Invest. 2007 Mar;117(3):514-21
17332878
J Immunol. 2007 Apr 1;178(7):4250-9
17371981
J Immunol. 2008 Nov 15;181(10):7390-9
18981162
J Pathol. 2008 Jan;214(2):260-6
18161747
Proc Natl Acad Sci U S A. 1997 May 13;94(10):5261-6
9144225
Rheumatology (Oxford). 2007 May;46(5):742-51
17202177
J Gastroenterol. 2006 Apr;41(4):318-24
16741610
Science. 2004 Oct 8;306(5694):271-5
15358865
Histol Histopathol. 2007 Nov;22(11):1251-67
17647198
Gastroenterology. 2003 Feb;124(2):521-36
12557156
J Environ Pathol Toxicol Oncol. 2004;23(2):79-97
15163287
Gut. 1989 Oct;30(10):1362-70
2511088
Immunity. 1999 Jan;10(1):39-49
10023769
Cardiovasc Res. 2005 Nov 1;68(2):268-77
15967421
J Immunol. 2008 Sep 15;181(6):4229-39
18768880
J Immunol. 2002 May 15;168(10):5342-51
11994493
J Exp Med. 2001 Nov 5;194(9):1207-18
11696587
Inflamm Bowel Dis. 2007 Feb;13(2):219-24
17206685
J Exp Med. 1998 Apr 20;187(8):1355-60
9547347
J Immunol. 2004 Nov 1;173(9):5757-65
15494528
Gut. 1989 Jun;30(6):826-34
2753407
Annu Rev Immunol. 2002;20:495-549
11861611
Blood. 2008 Jun 15;111(12):5694-703
18316626
Gut. 1993 Dec;34(12):1705-9
8031350
Dig Dis Sci. 2003 Feb;48(2):408-14
12643623
Microvasc Res. 2006 Jan;71(1):20-31
16337972
J Immunol. 2007 Dec 1;179(11):7344-51
18025177
Immunity. 2008 Jul 18;29(1):12-20
18631453
Immunol Rev. 2001 Jun;181:215-22
11513143
Am J Physiol Gastrointest Liver Physiol. 2008 Mar;294(3):G770-7
18202111
J Allergy Clin Immunol. 2008 Dec;122(6):1200-1207.e1
19084112
Adv Immunol. 2005;88:161-92
16227090
Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2446-51
9482905