The host has numerous pathways to mitigate the generation of oxidants, centering around the transcription factor
Nrf2 and its many downstream targets that promote the anti-oxidant response
[39]. One of the metabolites that is released into the airway in response to infection is itaconate, which activates
Nrf2 signaling under LPS stress
[40]. Itaconate is a dicarboxylate, structurally similar to both succinate and other TCA cycle determinants and a major metabolite found in the CF airway
[41]. In addition to its inhibition of macrophage SDH, itaconate also blocks glycolysis by altering the enzymatic function of both aldolase
[42] and glyceraldehyde 3-phosphate dehydrogenase
[43] (
Figure 2). Itaconate functions as a major immuno-regulatory molecule that resolves inflammation by modulating macrophage metabolism. Itaconate also dampens IL-1β release by blocking NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) activation
[44]. These effects seem to be mediated through NLRP3 decarboxypropylation on cysteine 548 (C548), which is expected to reduce NLRP3 interaction with NEK7, a major inflammasome regulator
[44].
Figure 2. Itaconate controls both host and bacteria metabolism. Itaconate, synthetized by mitochondrial IRG1, inhibits host cell metabolism at different levels. Itaconate can block GADPH, aldolase and the NLRP3-NEK7 complex, which participate in pro-inflammatory signaling. Itaconate also interferes with SDH function, which is required to promote IL-1β synthesis. Once secreted, itaconate blocks the glyoxylate shunt pathway in P. aeruginosa by blocking aceA activity. In S. aureus, itaconate inhibits aldolase, suppressing glycolysis and bacterial proliferation.
Itaconate is abundantly produced by macrophages and the host airway after infection with
P. aeruginosa [21,41][21][41]. Itaconate is toxic to many bacterial species, such as
Staphylococcus aureus, Mycobacterium tuberculosis and
Legionella pneumophila [45,46,47][45][46][47] targeting the activity of both isocitrate lyase (
aceA)
[48] and aldolase, major metabolic nodes that control the function of the anti-oxidant glyoxylate shunt
[49,50][49][50] and glycolysis, respectively (
Figure 2). However, several important airway pathogens, including
P. aeruginosa, M. tuberculosis and Aspergillus species can also metabolize itaconate
[51].
CF-adapted strains of
P. aeruginosa demonstrated adaptation to itaconate using it as a carbon source, instead of succinate
[41].
P. aeruginosa harbor three genes devoted to itaconate metabolism: namely,
ict,
ich and
ccl. Expression of these genes is upregulated in response to itaconate, and this loci catabolizes itaconate to produce acetyl-CoA and pyruvate, which fuel OXPHOS function, energy production and generation of biofilm
[41,51][41][51]. Itaconate is activated for degradation by
ict, which produces itaconyl-CoA. Then, in a two-steps reaction
ich first transforms itaconyl-CoA into its isomer mesaconyl-CoA to then hydrate it to form (
S)-citramalyl-CoA. Finally,
ccl breaks down (
S)-citramalyl-CoA to acetyl-CoA and pyruvate, proving the bacteria with pro-energetic intermediates. Clinical isolates from chronic infection, in which itaconate is plentiful, become adapted to both induce and prefer itaconate metabolism, as the clinical strains become impaired in their ability to infect
Irg1-/- mice
[41]. Interestingly, pneumonia caused by a laboratory PAO1 strain, which prefers succinate over itaconate, is independent of host
Irg1 function, illustrating how in vivo adaptation modulates both the immunostimulatory and metabolic preferences of these organisms.