A novel pathway for inducible nitric-oxide synthase activation through inflammasomes.
Innate immune recognition of flagellin is shared by transmembrane TLR5 and cytosolic Nlrc4 (NOD-like receptor family CARD (caspase activation recruitment domain) domain containing 4)/Naip5 (neuronal apoptosis inhibitory protein 5). TLR5 activates inflammatory genes through MYD88 pathway, whereas Nlrc4 and Naip5 assemble multiprotein complexes called inflammasomes, culminating in caspase-1 activation, IL-1β/IL-18 secretion, and pyroptosis. Although both TLR5 and Naip5/Nlrc4 pathways cooperate to clear infections, little is known about the relative anti-pathogen effector mechanisms operating through each of them. Here we show that the cytosolic flagellin (FLA-BSDot) was able to activate iNOS, an enzyme previously associated with TLR5 pathway. Using Nlrc4- or Naip5-deficient macrophages, we found that both receptors are involved in iNOS activation by FLA-BSDot. Moreover, distinct from extracellular flagellin (FLA-BS), iNOS activation by intracellular flagellin is completely abrogated in the absence of caspase-1. Interestingly, IL-1β and IL-18 do not seem to be important for FLA-BSDot-mediated iNOS production. Together, our data defined an additional anti-pathogen effector mechanism operated through Naip5 and Nlrc4 inflammasomes and illustrated a novel signaling transduction pathway that activates iNOS.
Buzzo
Carina L
CL
Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-900, Brazil.
Campopiano
Julia C
JC
Massis
Liliana M
LM
Lage
Silvia L
SL
Cassado
Alexandra A
AA
Leme-Souza
Rafael
R
Cunha
Larissa D
LD
Russo
Momtchilo
M
Zamboni
Dario S
DS
Amarante-Mendes
Gustavo P
GP
Bortoluci
Karina R
KR
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D005408:Flagellin / Q000276:immunology / Q000494:pharmacology; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D020382:Interleukin-18; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D046912:Multiprotein Complexes; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C496806:Naip5 protein, mouse; D051616:Neuronal Apoptosis-Inhibitory Protein; D051198:Toll-Like Receptor 5; D005408:Flagellin; D052247:Nitric Oxide Synthase Type II