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. Author manuscript; available in PMC: 2025 Mar 1.
Published in final edited form as: J Immunol. 2024 Mar 1;212(5):765–770. doi: 10.4049/jimmunol.2300418

Cytosolic receptor AIM2 is induced by PPARγ following M. tuberculosis infection of human macrophages but does not contribute to IL-1β release

Eusondia Arnett *,2, Jade Wolff 3, Chrissy M Leopold Wager *, Jan Simper *,†, Jeanine L Badrak *,4, Carlos Ontiveros *,†, Bin Ni 5, Larry S Schlesinger *,2
PMCID: PMC10922714  NIHMSID: NIHMS1957222  PMID: 38251918

Abstract

AIM2, an inflammasome component, mediates IL-1β release in murine macrophages and cell lines. AIM2 and IL-1β contribute to murine control of M. tuberculosis (M.tb) infection, but AIM2’s impact in human macrophages, the primary niche for M.tb, remains unclear. We show that M.tb, M. bovis BCG and M. smegmatis (M.sm) induce AIM2 expression in primary human macrophages. M.tb-induced AIM2 expression is PPARγ-dependent and M.tb ESX-1-independent whereas BCG- and M.sm-induced AIM2 expression is PPARγ-independent. PPARγ and NLRP3, but not AIM2, are important for IL-1β release in response to M.tb, and NLRP3 colocalizes with M.tb. This is in contrast to the role for AIM2 in inflammasome activation in mice and peritoneal macrophages. Altogether, we show that mycobacteria induce AIM2 expression in primary human macrophages but AIM2 does not contribute to IL-1β release during M.tb infection, providing further evidence that AIM2 expression and function are regulated in a cell- and/or species-specific manner.

Introduction

Tuberculosis (TB) is the number one infectious disease killer in human history, accounting for over 1 billion deaths with 1.6 million people dying annually (1). There has been a push to develop host-directed therapies (HDTs) for infectious diseases, including TB (2). However, development of bona fide targeted HDTs requires increased understanding of the host response to M.tb, particularly in humans. M.tb is phagocytosed by macrophages which provide the primary niche for intracellular growth (3). The initial macrophage response to M.tb is triggered through cell surface receptors, including TLRs and C-type lectins like the mannose receptor (CD206). CD206 is a key phagocytic receptor of human macrophages that is co-opted by M.tb, in part to activate Peroxisome Proliferator Activated Receptor Gamma (PPARγ) to enable intracellular growth (3–5). The M.tb phagosome is leaky, releasing M.tb components into the cytosol (6) where they can be recognized by cytosolic receptors including nucleotide binding oligomerization domain-containing protein (NOD)-like receptors (NLRs) and absent in melanoma 2 (AIM2), which regulate inflammasome activation (3, 7–9). Inflammasomes are multi-protein complexes that canonically require 2 signals for activation. Signal 1 (priming) is typically provided by TLRs and drives expression of pro-IL-1β. Signal 2 initiates formation of the inflammasome complex: NLRs or AIM2, the adapter molecule apoptosis associated speck-like protein containing a CARD (ASC), and pro-caspase-1. This leads to cleavage and release of IL-1β and IL-18 (7–9).

Single nucleotide polymorphisms (SNPs) in AIM2, NLRP3 and IL1B are associated with risk and type of TB (10, 11). Mice lacking IL1B, caspase-1, ASC, or AIM2 show increased susceptibility to M.tb and Mycobacterium bovis bacillus Calmette-Guérin (BCG) (12–14) yet the role of AIM2 during M.tb infection of primary human macrophages, the most relevant niche for human-adapted M.tb, remains unclear. In vitro results suggest M.tb drives AIM2 expression in Thp1 cells, a human monocyte/macrophage like tumor cell line (15) but doesn’t affect AIM2 expression in murine bone marrow-derived dendritic cells (BMDCs) (16) while M. bovis drives AIM2 expression in murine macrophages (17). AIM2 is important for IL-1β release during M.tb infection of murine peritoneal macrophages (12), but not murine BMDCs (16) or BMDMs (18) and there are conflicting reports on the role of AIM2 in Thp1 cells during M.tb infection (15, 19). Since cell type and species-specific functions influence inflammasome and AIM2 activity (7, 20–22) we sought to determine whether M.tb regulates AIM2 expression and if AIM2 contributes to inflammasome activation and IL-1β release specifically in human macrophages.

We show that M.tb, BCG, and M.sm drive AIM2 expression in primary human macrophages and this is PPARγ-dependent and IFN/M.tb ESX-1-independent for M.tb, but PPARγ-independent for BCG and M.sm. Strikingly, although AIM2 expression is increased, it is not involved in IL-1β release in response to M.tb or DNA, a canonical AIM2 activator, in contrast to findings in mice and peritoneal macrophages. Instead, PPARγ is important for IL1B expression and release, and M.tb- and DNA-mediated IL-1β release relies on NLRP3, which colocalizes with M.tb. This work provides further evidence that AIM2 expression and function are regulated in a cell and/or species specific manner, and that more work is required to understand AIM2’s impact during M.tb infection of primary human macrophages.

Material and Methods

Macrophage isolation

MDMs and AMLs were prepared from PBMCs, isolated from healthy adult blood following Ohio State University (OSU) and Texas Biomed approved Institutional Review Board (IRB) protocols 2003H0155 and HSC20170315H, respectively (23–25). Human AMs were freshly isolated from bronchoalveolar lavage of healthy adult human donors (25), following OSU approved IRB protocol 2015H0267. All donors provided informed, written consent. BMDMs were obtained from 8–9-week-old female C57BL/6 mice (Jackson Laboratory) (26).

Gene knockdown (KD)

Macrophages were transfected with siRNA using TransIT-X2 (Mirus Bio)(24)(Supplemental Table I).

Bacterial Strains

M.tb H37Rv (27294), BCG (35734), and M.sm (700084) were obtained from ATCC. M.tb Erdman and the previously validated ΔESX-1 (13.2 ΔEccCab) and ΔESX-1 complement (ORG12) were kind gifts from Dr. Jeffrey Cox (Berkeley, CA). Killed mycobacteria were prepared by incubating with 4% paraformaldehyde (PFA) for 20 min at room temperature, then washed with PBS (27).

Infection

MDMs were infected with single cell mycobacteria for 2h (23, 24) then washed and incubated in RPMI with 2% autologous serum or fixed with 4% PFA (27) to assess M.tb, BCG, and M.sm association with macrophages. Mycobacteria were then stained with auramine-rhodamine (BD Biosciences). Coverslips were imaged with a fluorescence microscope and number of mycobacteria per MDM was assessed for at least 100 MDMs in each condition. M.sm associated with MDMs 5x less efficiently than BCG or M.tb; therefore, unless otherwise indicated, MDMs were infected with MOI 25 M.sm and MOI 5 M.tb or BCG, which led to a similar number of mycobacteria/MDM (Supplemental Fig 1A).

Treatment to activate/inhibit inflammasomes

Classical AIM2 activation: Cells were treated with 1 μg/ml LPS (Sigma) for 1h, then transfected with poly(dA:dT) (Sigma) using Lipofectamine LTX with Plus Reagent (Invitrogen) for 6h. Classical NLRP3 activation: Cells were treated with 1 μg/ml LPS for 3h, then 5 mM ATP for 30 min. NLRP3 inhibition: MDMs were treated with the NLRP3 inhibitor MC9550 (10 μM) for the last 1h of LPS treatment and this was maintained during poly(dA:dT) or ATP stimulation.

RNA isolation and gene expression

Macrophages were lysed with TRIzol (Invitrogen) and total RNA was isolated (24). Gene expression was determined by quantitative real-time Reverse Transcription PCR (qRT-PCR) using TaqMan Gene Expression Assays (Applied Biosystems) in the Applied Biosystems 7500 Real-Time PCR System. Relative expression was calculated by the ΔΔCT method using β-actin as the housekeeping gene. AmpliSeq data was collected from Sadee et al. 2023 Res Sq.

Western blot (WB)

Cells were lysed with TN1 (24). WB was performed using antibodies against AIM2 (Abcam ab93015, Cell Signaling 12948 and 63660), PPARγ (Cell Signaling 2435) and β-actin (Cell Signaling 5125) and bands quantified with VisionWorks (Analytik Jena).

ELISA

Cell free supernatants were probed for IL-1β following the manufacturer’s instructions (R&D Systems).

NLRP3 staining

MDMs on coverslips were fixed with 4% PFA, permeabilized with methanol, then stained with NLRP3 antibodies (Proteintech 19771–1-AP) and nuclei were stained with DAPI (Invitrogen). Coverslips were mounted with ProLong Gold Antifade (Invitrogen) and imaged with a Zeiss LSM 800 confocal microscope.

Statistical Analysis

A minimum of three independent experiments, with cells from at least three different human donors were performed, unless indicated otherwise. Due to donor variability, results from each experiment were normalized to an internal control and a t-test or ANOVA was performed on the normalized data, with P < 0.05 considered significant, see figure legends for details.

Results & Discussion

M.tb induces AIM2 in human macrophages in a PPARγ-dependent manner

The impact of mycobacteria infection on AIM2 expression in primary human macrophages, its primary niche (3), is unknown. We queried if M.tb would affect AIM2 expression in three different primary human macrophages: human alveolar macrophages (AMs), monocyte-derived macrophages (MDMs), and AM-like macrophages (AMLs) (25). AIM2 gene expression was significantly increased in human AMs, MDMs, and AMLs following M.tb infection (Fig 1A,B, Supplemental Fig 1B), corresponding with increased AIM2 protein levels, with a significant increase after 24h (Fig 1C,D, Supplemental Fig 1C,D).

Fig 1. M.tb induction of AIM2 expression in primary human macrophages is PPARγ-dependent.

Fig 1.

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A-D) Human AMs (A) and MDMs (B-D) were infected with M.tb. Total RNA was collected and subjected to AmpliSeq (A) or qRT-PCR (B) or total protein was collected and subjected to WB (C), followed by densitometry analysis (D). Results are presented as AIM2 expression relative to uninfected control, mean ± SEM of n = 12 (A), ≥ 3 (D), or mean ± SD, representative of n ≥ 2 (B). E-F) MDMs were transfected with PPARγ (siP) or scrambled control (sc) siRNA then infected with M.tb. After 24h, lysates were collected and WB performed. Transfection did not alter basal expression of PPARγ, canonical PPARγ regulated genes (not shown), or basal or M.tb-induced AIM2 expression (Supplemental Fig 3F). Densitometry analysis results shown as AIM2 levels relative to M.tb-infected scrambled control. Results are the mean ± SEM, n = 5. A-F) One-way ANOVA with Dunnett’s post-test, * p < 0.05, ** p < 0.01, **** p < 0.0001.

Since AIM2 expression is classically thought to be driven through IFNs (7, 28, 29), we wondered if IFNs were important for M.tb-driven AIM2 expression. To assess this, we infected macrophages with a M.tb strain unable to drive IFN responses due to a deletion of ESX-1 (6, 30). ESX-1 deficient M.tb induced AIM2 expression to a similar extent as wild type M.tb (Supplemental Fig 1E,F), indicating that AIM2 expression is not ESX-1, IFN-dependent. The AIM2 promoter contains PPARγ binding sites, suggesting AIM2 expression may be regulated by PPARγ, a transcription factor that is activated by M.tb (3, 5). Indeed, PPARγ KD abrogated M.tb-driven AIM2 mRNA and protein expression (Fig 1E,F, Supplemental Fig 1G,H). Altogether, we show that M.tb drives AIM2 expression in primary human macrophages, in a PPARγ-dependent and ESX-1-independent manner, and identify AIM2 as a novel PPARγ effector.

Less virulent mycobacteria induce AIM2 expression in human macrophages, in a PPARγ-independent manner

We previously showed that M.tb, but not attenuated BCG or avirulent M.sm, activate PPARγ (5). Since PPARγ is critical for AIM2 expression in human macrophages (Supplemental Fig 1G,H, Fig 1E,F), we wondered if less virulent mycobacteria that do not activate PPARγ would be unable to drive AIM2 expression in human macrophages. Interestingly, both M.sm and BCG increased AIM2 expression (Fig 2A,B) at a range of MOIs (Supplemental Fig 1I,J). In contrast to M.tb, M.sm and BCG driven AIM2 expression was PPARγ–independent (Fig 2C,D).

Fig 2. M.sm and BCG induction of AIM2 expression is PPARγ-independent.

Fig 2.

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A,B) MDMs were infected with M.sm, BCG, or M.tb, then lysates were collected and WB performed. Densitometry analysis shown as AIM2 levels relative to the time matched uninfected samples, mean ± SEM ≥ 8, Two-way ANOVA with Tukey’s post-test, * p < 0.05, ** p < 0.01. C,D) MDMs were transfected with PPARγ (siP) or scrambled control (sc) siRNA then infected with M.sm, BCG or M.tb. After 24h, lysates were collected and WB performed. Densitometry analysis shown as AIM2 levels relative to the respective infected scrambled control. Results are the mean ± SEM, n = 3, unpaired two-tailed t-test of sc compared to siP, * p < 0.05. Similar findings were observed with infections at lower MOI (not shown).

We next determined if mycobacteria induction of AIM2 expression required live bacteria. Live and fixed M.tb and BCG induced AIM2 to a similar extent (Supplemental Fig 1K,L). This was expected for M.tb, since M.tb ManLAM exposure is retained after fixation, and ManLAM binds CD206 to drive PPARγ activity (5, 27). BCG may also signal at the plasma membrane to drive AIM2 expression, although not through PPARγ (Fig 2C,D). In contrast, fixed M.sm induced significantly less AIM2 expression than live M.sm (Supplemental Fig 1K,L). M.sm induction of IL-1β release is ESX-1- and IFN-dependent in murine DCs (16), and active secretion through ESX-1 leading to IFNs may be the mechanism for M.sm induction of AIM2 expression in human macrophages. Thus, three different mycobacteria species drive AIM2 expression in primary human macrophages, albeit through distinct signaling pathways, similar to what we reported for IL-8; whereby M.tb-driven IL-8 expression required PPARγ and BCG-driven IL-8 was NF-kB-dependent (5). Our findings reinforce the need to consider mycobacteria- and host-species specific effects.

PPARγ, but not AIM2, is important for IL-1β release in human macrophages

We next determined the impact of PPARγ and AIM2 on the inflammasome during M.tb infection of primary human macrophages. Using NanoString we previously observed that PPARγ KD led to reduced expression of genes involved in IL-1 signaling: IL1B, IL1A, and IL1 Receptor accessory protein (IL1RAP) (24). Here, we validated those findings and confirmed that PPARγ is important for M.tb-driven IL1B, IL1A and IL1RAP expression (Fig 3A–C). We also observed that PPARγ is important for M.tb-induced IL-1β release (Fig 3D). Similar findings have been reported in murine peritoneal macrophages, where PPARγ was important for IL1B and IL1A expression following lipid or ATP simulation (31) whereas it limited IL-1β release in rat neurons (32), suggesting a cell type and/or species specific role for PPARγ and IL-1 signaling. Altogether, our results indicate that PPARγ promotes IL-1 signaling in human macrophages during M.tb infection.

Fig 3. PPARγ regulates genes involved in IL-1 signaling and IL-1β release during M.tb infection.

Fig 3.

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MDMs were transfected with PPARγ (siP) or scrambled (sc) siRNA then infected with M.tb. After 24h, RNA was collected for qRT-PCR (A-C) and supernatants were probed for IL-1β (D). Transfection did not alter basal or M.tb-induced IL1A or IL1B expression (Supplemental Fig 3G). Results are mean ± SEM n ≥ 3, One-way ANOVA with Dunnett’s post-test, * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001.

AIM2 is important for IL-1β release in mice and peritoneal macrophages in response to M.tb or BCG infection (12, 13, 33), but the role of AIM2 in human macrophages during M.tb infection remains unclear. Thus, we determined if AIM2 regulates inflammasome activation and IL-1β release by primary human macrophages. We transfected MDMs with AIM2 specific siRNA which resulted in 78.5 ± 6.8 % KD and reduced AIM2 expression to below basal levels (Supplemental Fig 2A). However, AIM2 KD did not reduce IL-1β release by human macrophages during M.tb infection. In fact, we observed significantly increased IL-1β release with AIM2 KD (Fig 4A). To validate these findings, we repeated the experiment but used two different AIM2 siRNA sequences that recognize different regions of AIM2 RNA. Consistent with our initial findings, transfection with the two alternative AIM2 specific siRNAs (si6 and si7) led to a significant reduction in AIM2 expression to below basal levels (Supplemental Fig 2B) but did not reduce IL-1β release (Fig 4B). This indicates that AIM2 is not important for IL-1β release during M.tb infection of primary human macrophages, and may instead potentially inhibit the inflammasome. AIM2 is also not important for IL-1β release in murine BMDCs and BMDMs during M.tb infection (16, 18), indicating that AIM2 may not be involved in canonical inflammasome activity and IL-1β release during M.tb infection in both human and murine macrophages.

Fig 4. AIM2 does not regulate IL-1β release during M.tb infection.

Fig 4.

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MDMs were transfected with scrambled (sc) or three different AIM2 specific (si5, si6, si7) siRNA then infected with M.tb for 6h. Supernatants were probed for IL-1β. Results are mean ± SEM, n = 3 (A) or 2 (B), One-way ANOVA with Dunnett’s post-test, * p < 0.05, ** p < 0.01.

DNA is the canonical AIM2 inflammasome activator, so we next determined if AIM2 was required for IL-1β release in human macrophages in response to DNA. AIM2 KD did not reduce DNA induced IL-1β release (Supplemental Fig 2C–E). This is in contrast to the reported role of AIM2 in DNA-driven IL-1β release in murine macrophages, Thp1 cells, and MDMs (22, 28, 29, 34, 35). We wondered if this was due to differences in technique – since we used siRNA to KD AIM2 whereas most murine macrophage work used BMDMs isolated from AIM2 knockout mice. However, as previously reported, siRNA KD of AIM2 in BMDMs resulted in a significant reduction in IL-1β release in response to DNA stimulation (Supplemental Fig 2F,G). Altogether, this indicates that AIM2 drives inflammasome activation in murine, but not human macrophages and suggests that AIM2 may have a different role in human macrophages.

NLRP3 is important for IL-1β release in human macrophages

Since AIM2 was not required for DNA-driven IL-1β release in human macrophages, we next queried if NLRP3 was. We treated primary human macrophages with a NLRP3 specific inhibitor, then treated with DNA or ATP, canonical AIM2 and NLRP3 activators, respectively. As expected, NLRP3 inhibition significantly reduced IL-1β release in response to ATP, but also in response to DNA (Fig 5A). These results were also observed with NLRP3 KD (Supplemental Fig 3A). This is in agreement with a recent report that NLRP3 is important for DNA induced IL-1β release in primary human monocytes and macrophages (36).

Fig 5. NLRP3 regulates IL-1β release in response to DNA and M.tb, and colocalizes with M.tb in human macrophages.

Fig 5.

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A) MDMs were primed with LPS, and pre-treated with the NLRP3 inhibitor MC9550 for the last 1h of LPS priming, then stimulated with DNA [poly(dA:dT), 6h] or ATP (30 min). Supernatants were probed for IL-1β. Results are mean ± SD, representative of 2, unpaired two-tailed t-test, * p < 0.05, ** p < 0.01, *** p < 0.001. B) MDMs were transfected with scrambled (sc) or NLRP3 specific (siN) siRNA to achieve 74.8 ± 10.7 % KD then infected with M.tb for 6h. Supernatants were probed for IL-1β. Results are mean ± SEM of 2. One-way ANOVA with Dunnett’s post-test, **** p < 0.0001. C,D) MDMs were infected with mCherry M.tb (red) then cells were fixed and NLRP3 (green) and nuclei (blue) stained. Over 100 M.tb were counted to asses M.tb colocalization with NLRP3. C) Representative image of n=2, 2h, see Supplemental Fig 3E for additional images. D) Results are the mean ± SEM of 2.

We next confirmed that NLRP3 is important for M.tb-driven IL-1β release in primary human macrophages (Fig 5B), similar to previous reports (37–39). This corresponds with early M.tb-driven increases in NLRP3 expression and speck formation (Supplemental Fig 3B–D). Surprisingly, NLRP3 colocalized with M.tb, suggesting that it is recruited to the M.tb phagosome (Fig 5C, Supplemental Fig 3E). This was observed as early as 2h after infection, and maintained through at least 24h (Fig 5D). To our knowledge, this is the first example of M.tb colocalization with NLRP3, although AIM2 has been reported to colocalize with M.tb DNA in murine macrophages (12).

In summary, we find that, in contrast to murine DCs (16), M.tb, BCG, and M.sm drive AIM2 expression in primary human macrophages, similar to reports for Thp1 cells and murine macrophages (15, 17). In primary human macrophages, M.tb-induced AIM2 expression is PPARγ-dependent and IFN/M.tb ESX-1-independent, whereas BCG and M.sm driven AIM2 expression is PPARγ-independent. M.tb and BCG AIM2 induction is bacteria viability-independent whereas viable M.sm is required for AIM2 induction. In primary human macrophages, AIM2 is not involved in IL-1β release in response to M.tb or DNA, a canonical AIM2 activator. Instead, PPARγ is important for IL1B expression and release, and NLRP3 is important for DNA and M.tb-mediated IL-1β release and colocalizes with M.tb. Although IL-1β release during infection is the canonical role for AIM2, more recent work has also linked AIM2 to murine epithelial cell proliferation (22), autophagy in Thp1 cells and murine macrophages (40), and dampening the IFN response in murine macrophages (12, 13, 17, 41). Our work provides additional support that AIM2 behaves in a cell and species-specific manner, and that more work is critically needed to understand the role of AIM2 in primary human macrophages, the niche for M.tb.

Supplementary Material

1

Key Points.

  • M.tb induces AIM2 expression in a PPARγ-dependent and M.tb ESX-1-independent manner

  • PPARγ, not AIM2, is important for M.tb induced IL-1β release in human macrophages

  • NLRP3 colocalizes with M.tb and is important for IL-1β release in human macrophages

Acknowledgements

The authors thank Leonardo Aguilar and Sarah Mohammed for technical assistance and the Biocontainment Programs at Texas Biomed and OSU.

This work was supported by NIH awards AI136831, AI059639 to LSS, AI136831-02S1 and T32GM113896 to CO, T32HL007946 to EA, and 1P30AI168439 (EA, CMLW are participants in IN-TRAC, PI LSS). The funders had no role in design or implementation of the study, data collection, analysis, or preparation of the manuscript.

6. Abbreviations:

AIM2

absent in melanoma 2

AM

alveolar macrophage

AML

AM-like macrophage

ASC

the adapter molecule apoptosis associated speck-like protein containing a CARD

BCG

Mycobacterium bovis bacillus Calmette-Guérin

BMDC

bone marrow-derived dendritic cell

BMDM

bone marrow-derived macrophage

HDT

host-directed therapy

IL1RAP

IL1 Receptor accessory protein

IRB

Institutional Review Board

KD

knockdown

MDM

monocyte-derived macrophage

M.sm

M. smegmatis

M.tb

M. tuberculosis

NOD

nucleotide binding oligomerization domain-containing protein

NLR

NOD-like receptor

OSU

Ohio State University

PFA

paraformaldehyde

PPARγ

Peroxisome Proliferator Activated Receptor Gamma

SNPs

Single nucleotide polymorphisms

TB

Tuberculosis

WB

Western blot

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