Tissue-Resident Alveolar Macrophages Do Not Rely on Glycolysis for LPS-induced Inflammation

Woods, P.S.; Kimmig, Lucas; Meliton, Angelo Y.; Sun, K.; Tian, Yufeng; O’Leary, Erin; Gökalp, G.; Hamanaka, Robert B.; Mutlu, Gökhan M.

doi:10.1165/rcmb.2019-0244oc

Cited by 78 publications

(89 citation statements)

References 47 publications

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“…Lungs are the primary site of entry for PM, and we have previously demonstrated that alveolar macrophages (AMs) are metabolically distinct from BMDMs (Woods, Kimmig et al 2020). We thus sought to determine whether the role of itaconate in AMs is similar to what we observed in BMDMs.…”

Section: Itaconate Does Not Modulate Pm-induced Inflammation or Nrf2 mentioning

confidence: 99%

“…All animal experiments and procedures were performed according to the protocols approved by the Institutional Animal Care and Use Committee at the University of Chicago. We used primary murine cells (bone marrow-derived macrophages (BMDMs)), which we isolated as we have recently reported (Woods, Kimmig et al 2020 qRT-PCR primer sequences used are as follows:…”

Section: Cell Isolation and Culturementioning

confidence: 99%

“…The Seahorse XF e 24 Extracellular Flux Analyzer (Seahorse Bioscience, North Billerica, MA), was used to measure oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) as we have previously described (Nigdelioglu, Hamanaka et al 2016, Hamanaka, O'Leary et al 2019, Soberanes, Misharin et al 2019, Woods, Kimmig et al 2020).…”

Section: Seahorse Analysismentioning

confidence: 99%

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Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response

Sun

Meliton

et al. 2020

eLife

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Particulate matter (PM) air pollution causes cardiopulmonary mortality via macrophage-driven lung inflammation; however, the mechanisms are incompletely understood. RNA-sequencing demonstrated Acod1 (Aconitate decarboxylase 1) as one of the top genes induced by PM in macrophages. Acod1 encodes a mitochondrial enzyme that produces itaconate, which has been shown to exert anti-inflammatory effects via NRF2 after LPS. Here, we demonstrate that PM induces Acod1 and itaconate, which reduced mitochondrial respiration via complex II inhibition. Using Acod1-/- mice, we found that Acod1/endogenous itaconate does not affect PM-induced inflammation or NRF2 activation in macrophages in vitro or in vivo. In contrast, exogenous cell permeable itaconate, 4-octyl itaconate (OI) attenuated PM-induced inflammation in macrophages. OI was sufficient to activate NRF2 in macrophages; however, NRF2 was not required for the anti-inflammatory effects of OI. We conclude that the effects of itaconate production on inflammation are stimulus-dependent, and that there are important differences between endogenous and exogenously-applied itaconate.

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Section: Itaconate Does Not Modulate Pm-induced Inflammation or Nrf2 mentioning

confidence: 99%

Section: Cell Isolation and Culturementioning

confidence: 99%

Section: Seahorse Analysismentioning

confidence: 99%

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Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response

Sun

Meliton

et al. 2020

eLife

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“…All animal experiments and procedures were performed according to the protocols approved by the Institutional Animal Care and Use Committee at the University of Chicago. We used primary murine cells (bone marrow-derived macrophages (BMDMs), which we isolated as we have recently reported (Woods, Kimmig et al 2019). Hematopoietic cells were isolated from bone marrow of C57BL/6NJ (Stock No: 005304) and Acod1 -/- (…”

Section: Cell Isolation and Culturementioning

confidence: 99%

“…The Seahorse XF e 24 Extracellular Flux Analyzer (Seahorse Bioscience, North Billerica, MA), was used to measure oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) as we have previously described (Nigdelioglu, Hamanaka et al 2016, Soberanes, Misharin et al 2019, Woods, Kimmig et al 2019). Macrophages were seeded at a density of 4  10 4 per well on a Seahorse XF24 Cell Culture Microplate (Woods, Kimmig et al 2019).…”

Section: Seahorse Analysismentioning

confidence: 99%

Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response

Sun

Meliton

et al. 2020

Preprint

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ABSTRACTParticulate matter (PM) air pollution causing significant cardiopulmonary mortality via macrophage-driven lung inflammation; however, the mechanisms are not completely understood. RNA-sequencing demonstrated Acod1 (Aconitate decarboxylase 1) as one of the top genes induced by PM in macrophages. Acod1 encodes a mitochondrial enzyme that produces itaconate, which has been shown to exert anti-inflammatory effects via NRF2 after LPS. Here, we demonstrate that PM induces Acod1 and itaconate, which reduced mitochondrial respiration via complex II inhibition. Using Acod1-/- macrophages, we found that Acod1/endogenous itaconate was not required for PM-induced inflammation or NRF2 activation. In contrast to endogenous itaconate, exogenous cell permeable form of itaconate (4-octyl itaconate (OI)) attenuated the PM-induced inflammation and activated NRF2 but NRF2 was not required for the anti-inflammatory effects of OI. We conclude that the effects of itaconate production on inflammation are stimulus-dependent, and that there are important differences between endogenous and exogenously-applied itaconate.

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March of Mycobacterium: miRNAs intercept host cell CD40 signalling

Chauhan

Dandapat

Sarkar³

et al. 2020

Clin & Trans Imm

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The disease tuberculosis is fatal if untreated. It is caused by the acid-fast bacilli Mycobacterium tuberculosis. Mycobacterium resides and replicates within the alveolar macrophages, causing inflammation and granuloma, wherein macrophage-T cell interactions enhance the inflammation-causing pulmonary caseous lesions. The first interactions between Mycobacterium and the receptors on macrophages decide the fate of Mycobacterium because of phagolysosomal impairments and the expression of several miRNAs, which may regulate CD40 expression on macrophages. While the altered phagolysosomal functions impede antigen presentation to the T cell-expressed antigen receptor, the interactions between the macrophage-expressed CD40 and the T cell-expressed CD40-ligand (CD40L or CD154) provide signals to T cells and Mycobacterium-infected macrophages. These two functions significantly influence the resolution or persistence of Mycobacterium infection. CD40 controls T-cell polarisation and host-protective immunity by eliciting interleukin-12p40, nitric oxide, reactive oxygen species and IFN-c production. Indeed, CD40deficient mice succumb to low-dose aerosol infection with Mycobacterium because of deficient interleukin (IL)-12 production leading to impaired IFN-c-secreting T-cell response. In contrast, despite generating fewer granulomas, the CD40L-deficient mice developed anti-mycobacterial T-cell responses to the levels observed in the wild-type mice. These host-protective responses are significantly subdued by the Mycobacterium-infected macrophage produced TGF-b and IL-10, which promote promycobacterial T-cell responses. The CD40-CD40L-induced counteractive immune responses against Mycobacterium thus present a conundrum that we explain here with a reconciliatory hypothesis. Experimental validation of the hypothesis will provide a rationale for designing anti-tubercular immunotherapy.

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Tissue-Resident Alveolar Macrophages Do Not Rely on Glycolysis for LPS-induced Inflammation

Cited by 78 publications

References 47 publications

Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response

Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response

Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response

March of Mycobacterium: miRNAs intercept host cell CD40 signalling

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