Danielli S , Ma Z , Pantazi E , Kumar A , Demarco B , Fischer FA , Paudel U , Weissenrieder J , Lee RJ , Joyce S , Foskett JK , Bezbradica JS .

MR/W001217/1 Medical Research Council , MR/S000623/1 Medical Research Council , R01 AI137082 NIAID NIH HHS , R03 TR003299 NCATS NIH HHS , R01 DC018278 NIDCD NIH HHS

             immune response
             innate immune response

	Synopsis CALHM6 is an immune synaptic ion channel that regulates the kinetics of natural killer (NK) cell activation during infection. Pro-inflammatory stimuli like Poly(I:C) and systemic Listeria monocytogenes infection activate macrophages to upregulate CALHM6 expression. Infected macrophages activate NK cells in the spleen through the formation of an immunological synapse to which CALHM6 is recruited. In Calhm6-deficient mice infected with L. monocytogenes, the production of IFN-γ and IL-10 from NK cells is delayed and the initial bacterial burden increased. Mouse CALHM6 expression in the membrane of Xenopus oocytes is toxic as the channel is constitutively open. Cells with reduced or transient mCALHM6 expression generate ion currents dependent on the conserved negatively charged residue E119.
	Figure 1. CALHM6 is upregulated by pro-inflammatory and downregulated by anti-inflammatory signals A. Calhm6 mRNA expression measured by qPCR in F4/80+ macrophages and CD11c+ DCs magnetically isolated from spleens of mice injected with Poly(I:C) (0.5 mg/mouse) or PBS for 6 h (Poly(I:C)-treated mice n = 3, control mice n = 3). B. Representative immunoblot analysis of CALHM6 expression in BMDM and BMDC stimulated for 6 or 24 h with Poly(I:C) (50 μg/ml) or LPS (100 ng/ml) (one representative experiment of two is shown, n = 2 mice). C. BMDM were stimulated for 6 or 24 h with LPS (100 ng/ml), Zymosan (100 μg/ml) or Poly(I:C) (50 μg/ml). Calhms mRNA expression measured by qPCR (one representative experiment of two is shown, n = 3 mice per experiment, total n = 6 mice, biological replicates). D. Representative immunoblot analysis of CALHM6 expression in BMDM stimulated with LPS (100 ng/ml) or IFN-γ (10 ng/ml) for 2–48 h (one representative experiment of three is shown, n = 3 mice). E. Calhms mRNA expression measured by qPCR in BMDM stimulated for 8 h with LPS (100 ng/ml), alone or together with recombinant TGF-β (10 ng/ml), IL-10 (10 ng/ml) or IL-4 (10 ng/ml) (one representative experiment of two is shown, n = 9 mice, biological replicates). F. Representative immunoblot analysis of CALHM6 expression in BMDM stimulated with LPS (100 ng/ml) or IFN-γ (10 ng/ml) with or without TGF-β (10 ng/ml) for 8 or 4 h (one representative experiment of three is shown, n = 3 mice). G, H. Calhm6 mRNA expression measured by qPCR in naïve or IFN-γ (10 ng/ml) primed (6 h) BMDM stimulated with (G) Poly(I:C) (50 μg/ml) (one representative experiment of two is shown, n = 2 mice, biological replicates), or (H) Zymosan (100 μg/ml) for 2–24 h (one representative experiment is shown, n = 3 mice, biological replicates).
	Figure 2. Calhm6−/− mice poorly control Listeria monocytogenes burden at the peak of infection A. Experimental scheme: WT and Calhm6−/− mice were injected i.p. with 3 × 105 CFU of L. monocytogenes. On day 1, 3 and 7, mice were sacrificed, spleens mechanically dispersed using beads, and cells grown on antibiotic-free BHI agar plates to determine CFUs. B–H. CFU/g of spleen are shown (B) after 24 h (pooled results from two independent experiments, WT mice = 9, Calhm6−/− mice = 12, Man Whitney test), (C) 72 h (pooled results from two independent experiments, WT mice = 16, Calhm6−/− mice = 17, Man Whitney test) and (E) 7 days (results from one experiment, WT mice = 7, Calhm6−/− mice = 8, Man Whitney test). (D) Weight loss monitored daily for 3 days post-inoculation (pooled results from two independent experiments, WT mice = 16, Calhm6−/− mice = 17, two-way ANOVA). Serum collected from infected mice at peak infection (day 3) and serum cytokines quantified using LEGENDplex Mouse Inflammation Panel assay to determine IFN-γ (F), IL-6 (G) and IL-10 (H) concentration (pooled results from two independent experiments, WT mice = 16, Calhm6−/− mice = 17, Mann–Whitney test).
	Figure EV1. Generation and characterisation of Calhm6−/− mice
	Figure 3. Calhm6−/− mice have delayed NK cell activation in response to Listeria monocytogenes infection and to Poly(I:C) in vivo A–E. WT and Calhm6−/− mice were injected IP with 3 × 105 CFU of L. monocytogenes or PBS. After 18 h (A–C) or 3 days (D, E) spleens were collected and splenocytes incubated for an additional 4 h with Brefeldin A before intracellular staining for IFN-γ and analysis by flow cytometry. (A, D) Representative contour plots, (B, E) pooled frequency of IFN-γ+ cells in CD3−NK1.1+ cells gate from WT and Calhm6−/− mice, and (C) normalised to 1 IFN-γ+ cells that are NK1.1+ or CD3+ based on WT, to pool experiments (For Lm 18 h: pooled results from four independent experiments, Poly(I:C) WT mice = 16, Calhm6−/− mice = 17, control WT mice = 5, Calhm6−/− mice = 5, One way ANOVA with multiple comparisons. For Lm 3 days: pooled results from two independent experiments, WT mice = 8, Calhm6−/− mice = 9, Mann–Whitney test). F–J. WT and Calhm6−/− mice were injected i.p. with Poly(I:C) (200 μg/mouse) or PBS for 3 h (F–H) or 12 h (I, J), spleens were collected and processed as in (A–E). Representative contour plots (F, I), pooled frequency of IFN-γ+ in CD3−NK1.1+ cells of WT versus Calhm6−/− mice (G, J) and ratio of IFN-γ+ cells that are NK1.1+ or CD3+ normalised as in C (H) (For Poly(I:C) 3 h: pooled results from two independent experiments, Poly(I:C) WT mice = 10, Calhm6−/− mice = 10, control WT mice = 2, Calhm6−/− mice = 2, One way ANOVA with multiple comparisons. For Poly(I:C) 12 h: results from one experiment, Poly(I:C) WT mice = 6, Calhm6−/− mice = 5, control WT mice = 1, Calhm6−/− mice = 1 mice, One-way ANOVA with multiple comparisons).
	Figure 4. Calhm6−/− macrophages and NK cells are capable of normal responses to activating signals when stimulated in isolation, in vitro A, B. WT and Calhm6−/− mice were injected i.p. with Poly(I:C) (200 μg/mouse) or PBS. On day 3 spleens were collected, stained with antibodies against NK cell-maturation markers and analysed by flow cytometry. Representative contour plots (A) and pooled flow cytometry results (B) are shown (results from one experiment, Poly(I:C) WT mice = 5, Calhm6−/− mice = 5, control WT mice = 2, Calhm6−/− mice = 2 mice, One-way ANOVA with multiple comparisons). C. CD3−NK1.1+ cells were isolated from naïve mouse spleens and stimulated in vitro with PMA/ionomycin, IL-12 (50 ng/ml), TNF (50 ng/ml), or IL-18 (50 ng/ml). After 6 h stimulation, supernatant was collected and IFN-γ was measured by ELISA (pooled results from two independent experiments, Untreated and PMA stimulation WT mice = 6, Calhm6−/− mice = 6, TNF + IL-12 stimulation: WT mice = 3, Calhm6−/− mice = 3, otherwise WT mice = 3, Calhm6−/− mice = 2, One-way ANOVA with multiple comparisons). D, E. BMDM with or without 24 h IFN-γ priming were grown in antibiotic-free medium, washed and cultured with Listeria monocytogenes (MOI 1) for 30 min, at which time gentamicin (5 ng/ml) was added to the medium to kill extracellular bacteria. Supernatant from BMDM infected with L. monocytogenes was collected after 6 h. IL-1β (D, pooled results from five independent experiments, WT mice = 5, Calhm6−/− mice = 5, Kruskal–Wallis test) and IL-18 concentration (E, pooled results from three independent experiments, WT mice = 3, Calhm6−/− mice = 3, Kruskal–Wallis test) were quantified by ELISA, and normalised to WT set to 100%, to allow pooling of independent experiments. F. NO production in WT and Calhm6−/− BMDM treated overnight with LPS or Poly(I:C) quantified with a Griess test on cell supernatant (results from one experiment, WT mice = 3, Calhm6−/− mice = 3, Kruskal–Wallis test with multiple comparisons). G. BMDM with or without IFN-γ priming were grown overnight in antibiotic-free medium. Cells were infected with L. monocytogenes (MOI 1) for 30 min. Gentamicin (5 ng/ml) was then added to the medium to kill extracellular bacteria. At 0, 4 and 8 h cells were harvested, lysed with 0.1% Triton X-100 and the lysate was plated on antibiotic-free BHI plates for 24 h, and CFU were quantified (pooled results from three independent experiments, WT mice = 3, Calhm6−/− mice = 3, Two-way ANOVA test).
	Figure EV2. Calhm6−/− macrophages have a normal type I IFN response to Poly(I:C) injection
	Figure EV3. CALHM6 on CD11c+ dendritic cells is dispensable for NK cell activation and IFN-γ production
	Figure 5. CALHM6 is recruited to synapses formed by activated BMDMs A–C. BMDM were left untreated or stimulated for 24 h with Poly(I:C) (10 μg/ml) before RNA extraction and bulk RNASeq analysis. (A, B) Volcano plot of differentially expressed genes between untreated (A) or Poly(I:C) stimulated (B) WT and Calhm6−/− BMDM. (C) Bubble plot of Gene Ontology analysis of DEGs from poly(I:C) stimulated WT and Calhm6−/− BMDM (results from one experiment, WT mice = 3, Calhm6−/− mice = 3). D–G. BMDM were transduced with a retroviral vector expressing CALHM6-eGFP. BMDM (3 × 105) were plated on coverslips and pre-treated with IFN-γ and LPS for 6 h. (D) Freshly isolated primary CD3−NK1.1+ cells isolated from mouse spleens were added for 0, 10, 20, or 40 min on top of plated BMDMs that were generated from bone marrow cells transduced with a retroviral vector expressing CALHM6-eGFP. The interacting cells were then fixed and stained with phalloidin to identify actin and DAPI to identify nuclei. Synaptic interaction between BMDM and NK cell is indicated by white arrowheads; entire collapsed imaging Z-stack is shown. (E) Images were blinded and CALHM6-eGFP polarisation towards CD3−NK1.1+ cells manually scored only in Z-slices where BMDM-NK interaction was identified (P-value calculated by two-way ANOVA of polarisation and time points). Numbers on top of each bar indicate number of synapses scored for that time point. (F) IgG2a-opsonised sRBC labelled with PHK26 were added on top of plated CALHM-eGFP-expressing BMDM. One single Z-slice containing BMDM-sRBC interaction plane is shown. Synaptic interaction between BMDM and sRBC cell is indicated by white arrowheads (G) Quantified results of experiment in F. Numbers on top of each bar indicate number of synapses scored for that time point. Longer time points were not possible to score for opsonised sRBC because of the speed of the phagocytosis as sRBC were quickly internalised. Images taken with 60× objective (P-value calculated by two-way ANOVA of polarisation and time points).
	Figure EV4. CALHM6 is recruited to phagocytic synapse but is not required for phagocytosis
	Figure 6. CALHM6 forms a plasma membrane ion channel BMDM were stimulated for 24 h with IFN-γ (10 ng/ml) or LPS (100 ng/ml) and harvested in 1% digitonin or 1% DDT buffer, with cOmplete Protease Inhibitor Cocktail. The lysate was resolved by Native BluePAGE gel under non-denaturing conditions, and probed with anti-CALHM6 antibody (one representative experiment of two is shown, n = 3 mice). WT or Calhm6−/− BMDM stimulated with IFN-γ (10 ng/ml) for 24 h were lysed with 1% Triton X100-containing buffer with cOmplete Protease Inhibitor Cocktail and treated with increasing concentrations of DTT. The samples, without boiling, were resolved by SDS–PAGE gel (one representative experiment of two is shown, n = 4 mice). Lack of DTT influences solubilisation of GADPH monomer, and its detection for immunoblotting. WT-mCALHM6-GFP and E119R-mCALHM6-GFP localise to the plasma membrane of Xenopus oocytes. Upper: transmitted light image; Lower: confocal fluorescence image at oocyte equator (Images representative of three independent experiments, oocytes = 6). Expression of WT-mCALHM6 results in oocyte death 24 h after injection of either 5 ng (left) or 50 ng (middle) mCALHM6 cRNA, but oocytes injected with 50 ng E119R-mCALHM6 cRNA remain healthy (right) (Images representative of three independent experiments, oocytes = 5–10). Localisation of mCALHM6-eGFP in N2a cells 48 h post-transfection. mCALHM6 localises predominately in intracellular compartments (Images representative of three independent experiments, n = 7 cover glasses analysed). Representative families of currents recorded by two-electrode voltage-clamp in Xenopus oocytes, evoked by 3-s voltage pulses from −80 mV to +70 mV in 10-mV intervals from a holding potential of −15 mV in 2 mM Ba2+ bath solution. Left: currents in oocyte injected with WT-mCALHM6 cRNA; red current trace recorded at −80 mV from −15 mV holding potential after addition of 2 mM Gd3+; Middle: currents in oocyte expressing E119R-mCALHM6; Right: currents in oocyte injected with connexin 26 antisense oligonucleotide (ASO) only (control). Dashed line: zero-current level. Current–voltage (I-V) relations for WT-mCALHM6, E119R-mCALHM6 and control (ASO) in 2-mM Ba2+ bath solution (pooled individual whole-cell patches, WT-mCALHM6 n = 13, E119R-mCALHM6 n = 4, control = 4, SEM error bars).
	Figure 7. CALHM6 channel facilitates ATP release from activated macrophages Fura-2 fluorescence ratio (F340/380) recorded in N2a cells expressing human CALHM1 (hCALHM1), mouse CALHM6 (mCALHM6) or control (vector) in response to removal and subsequent add-back of extracellular Ca2+. Traces representative of four independent experiments for each, normalised to baseline ratio. Right: Resting F340/380 ratio in N2a cells expressing hCALHM1, mCALHM6 or vector in 2 mM Ca2+ (the error bars represent SEM). F340/380 ratio in response to Ca2+ add-back protocol in mouse BMDMs with and without stimulation by Poly(I:C) and LPS. Traces representative of four independent experiments for WT macrophages and three for Calhm6−/− macrophages. Right: Resting F340/380 ratio in WT and CALHM6-KO macrophages in 2 mM Ca2+ solution (the error bars represent SEM). Naïve or overnight IFN-γ-primed BMDM from WT and Calhm6−/− mice were exposed to isotonic medium containing 5 mM of EDTA (to chelate extracellular Ca2+) and 1 mM ATPase inhibitor ARL67156 (to prevent degradation of any released ATP) for 20 min. ATP concentration in the medium was measured with ENLITEN Luciferase/rLuciferin assay (pooled results from two independent experiments, WT mice = 4, Calhm6−/− mice = 4, one-way ANOVA with multiple comparisons). Plat-E cells were transfected with IRES-GFP-expressing plasmids containing only a HA-tag, CALHM6-HA, or CALHM1-HA. Ca2+ concentrations were acutely changed for 20 min in isotonic medium containing either EDTA or excess K+. ATP release was measured as described above (pooled results from three independent experiments, Calhm6−/− mice = 3, error bars represent SD). Steady-state ATP release from activated macrophages: BMDMs were plated at 150,000 cells/well in a 48-well plate, and incubated for 3 h with Poly(I:C) (50 μg/ml), LPS (100 ng/ml) and ATPase inhibitor ARL67156 (1 mM) in culture medium. Control cells were incubated with 1 mM ARL67156 only. ATP release (nM) measured using Sigma ATP Bioluminescent Assay: WT without stimulation: 9.12 ± 0.76; WT with stimulation: 22.16 ± 1.83; Calhm6−/− cells without stimulation: 8.76 ± 0.55; KO cells with stimulation: 12.19 ± 0.75 (pooled results from three independent experiments, WT mice = 3, Calhm6−/− mice = 3, Two-tailed unpaired Student's t-test, error bars represent SEM).
	Figure EV5. CALHM6 does not act as a chaperone for ATP receptor P2X7R and is not controlling P2X7R signalling in BMDM

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