IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy.
OBJECTIVE
Interleukin 33 (IL-33) is a new member of the IL-1 family of cytokines which signals via its receptor, ST2 (IL-33R), and has an important role in Th2 and mast cell responses. This study shows that IL-33 orchestrates neutrophil migration in arthritis.


RESULTS
Methylated bovine serum albumin (mBSA) challenge in the knee joint of mBSA-immunised mice induced local neutrophil migration accompanied by increased IL-33R and IL-33 mRNA expression. Cell migration was inhibited by systemic and local treatments with soluble (s)IL-33R, an IL-33 decoy receptor, and was not evident in IL-33R-deficient mice. IL-33 injection also induced IL-33R-dependent neutrophil migration. Antigen- and IL-33-induced neutrophil migration in the joint was dependent on CXCL1, CCL3, tumour necrosis factor alpha (TNFalpha) and IL-1beta synthesis. Synovial tissue, macrophages and activated neutrophils expressed IL-33R. IL-33 induces neutrophil migration by activating macrophages to produce chemokines and cytokines and by directly acting on neutrophils. Importantly, neutrophils from patients with rheumatoid arthritis successfully treated with anti-TNFalpha antibody (infliximab) expressed significantly lower levels of IL-33R than patients treated with methotrexate alone. Only neutrophils from patients treated with methotrexate alone or from normal donors stimulated with TNFalpha responded to IL-33 in chemotaxis.


CONCLUSIONS
These results suggest that suppression of IL-33R expression in neutrophils, preventing IL-33-induced neutrophil migration, may be an important mechanism of anti-TNFalpha therapy of inflammation.
Verri
Waldiceu A
WA
Department of Pharmacology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil. waverri@uel.br
Souto
Fabrício O
FO
Vieira
Silvio M
SM
Almeida
Sergio C L
SC
Fukada
Sandra Y
SY
Xu
Damo
D
Alves-Filho
Jose C
JC
Cunha
Thiago M
TM
Guerrero
Ana T G
AT
Mattos-Guimaraes
Rafaela B
RB
Oliveira
Fabíola R
FR
Teixeira
Mauro M
MM
Silva
João S
JS
McInnes
Iain B
IB
Ferreira
Sergio H
SH
Louzada-Junior
Paulo
P
Liew
Foo Y
FY
Cunha
Fernando Q
FQ
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D002630:Chemotactic Factors / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D018123:Receptors, Interleukin; D013583:Synovial Membrane / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D018501:Antirheumatic Agents; D002630:Chemotactic Factors; D016207:Cytokines; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D014409:Tumor Necrosis Factor-alpha